14-102016062-C-T

Variant names:

• chr14-102016062-C-T
• rs17541158
• NM_001376.5:c.7449C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001376.5(DYNC1H1):​c.7449C>T​(p.Ile2483Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 1,611,844 control chromosomes in the GnomAD database, including 1,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I2483I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (115 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1283 hom.)
• Consequence: DYNC1H1 NM_001376.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.629
• Publications: 10 publications found

Genes affected

DYNC1H1 (HGNC:2961): (dynein cytoplasmic 1 heavy chain 1) Dyneins are a group of microtubule-activated ATPases that function as molecular motors. They are divided into two subgroups of axonemal and cytoplasmic dyneins. The cytoplasmic dyneins function in intracellular motility, including retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Molecules of conventional cytoplasmic dynein are comprised of 2 heavy chain polypeptides and a number of intermediate and light chains.This gene encodes a member of the cytoplasmic dynein heavy chain family. [provided by RefSeq, Oct 2008]

DYNC1H1 Gene-Disease associations (from GenCC):

• autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
• intellectual disability, autosomal dominant 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• neuronopathy, distal hereditary motor

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease axonal type 2O

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 14-102016062-C-T is Benign according to our data. Variant chr14-102016062-C-T is described in ClinVar as Benign. ClinVar VariationId is 128941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.629 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	NM_001376.5	MANE Select	c.7449C>T	p.Ile2483Ile	synonymous	Exon 36 of 78	NP_001367.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	ENST00000360184.10	TSL:1 MANE Select	c.7449C>T	p.Ile2483Ile	synonymous	Exon 36 of 78	ENSP00000348965.4
	DYNC1H1	ENST00000681574.1		c.7449C>T	p.Ile2483Ile	synonymous	Exon 36 of 77	ENSP00000505523.1
	DYNC1H1	ENST00000679720.1		c.7449C>T	p.Ile2483Ile	synonymous	Exon 36 of 78	ENSP00000505938.1

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4816 AN: 152190 Hom.: 115 Cov.: 33

Gnomad AFR AF: 0.00772

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0302

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0324 AC: 8005 AN: 246886 AF XY: 0.0329

Gnomad AFR exome AF: 0.00661

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0863

Gnomad EAS exome AF: 0.000769

Gnomad FIN exome AF: 0.0469

Gnomad NFE exome AF: 0.0418

Gnomad OTH exome AF: 0.0412

GnomAD4 exome AF: 0.0385 AC: 56137 AN: 1459536 Hom.: 1283 Cov.: 32 AF XY: 0.0379 AC XY: 27510 AN XY: 725932

African (AFR) AF: 0.00718 AC: 240 AN: 33424

American (AMR) AF: 0.0234 AC: 1042 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.0856 AC: 2232 AN: 26080

East Asian (EAS) AF: 0.000379 AC: 15 AN: 39622

South Asian (SAS) AF: 0.0126 AC: 1086 AN: 85928

European-Finnish (FIN) AF: 0.0471 AC: 2478 AN: 52628

Middle Eastern (MID) AF: 0.0659 AC: 380 AN: 5766

European-Non Finnish (NFE) AF: 0.0416 AC: 46267 AN: 1111246

Other (OTH) AF: 0.0397 AC: 2397 AN: 60326

GnomAD4 genome AF: 0.0316 AC: 4812 AN: 152308 Hom.: 115 Cov.: 33 AF XY: 0.0319 AC XY: 2376 AN XY: 74462

African (AFR) AF: 0.00770 AC: 320 AN: 41574

American (AMR) AF: 0.0301 AC: 461 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0922 AC: 320 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4832

European-Finnish (FIN) AF: 0.0529 AC: 561 AN: 10608

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0435 AC: 2960 AN: 68016

Other (OTH) AF: 0.0369 AC: 78 AN: 2114

Alfa AF: 0.0369 Hom.: 268

Bravo AF: 0.0289

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 26, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 11, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 20, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Charcot-Marie-Tooth disease axonal type 2O Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Apr 14, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Autosomal dominant cerebellar ataxia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.3
DANN	Benign	0.73
PhyloP100		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17541158; hg19: chr14-102482399;