rs17541505

Positions:

• chr14-102038501-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001376.5(DYNC1H1):​c.10950C>T​(p.Asn3650=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0684 in 1,614,040 control chromosomes in the GnomAD database, including 4,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (325 hom., cov: 32)
  • Exomes 𝑓: 0.069 (3820 hom.)
• Consequence: DYNC1H1 NM_001376.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.05

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 14-102038501-C-T is Benign according to our data. Variant chr14-102038501-C-T is described in ClinVar as [Benign]. Clinvar id is 128927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102038501-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC1H1	NM_001376.5	c.10950C>T	p.Asn3650=	synonymous_variant	58/78	ENST00000360184.10	NP_001367.2
LOC107984661	XR_001750903.2	n.82+455G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.10950C>T	p.Asn3650=	synonymous_variant	58/78	1	NM_001376.5	ENSP00000348965	P1
	ENST00000553701.1	n.347-1732G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0609 AC: 9258 AN: 152064 Hom.: 326 Cov.: 32

Gnomad AFR AF: 0.0417

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0460

Gnomad ASJ AF: 0.0816

Gnomad EAS AF: 0.00713

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0954

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0694

Gnomad OTH AF: 0.0676

GnomAD3 exomes AF: 0.0676 AC: 16988 AN: 251386 Hom.: 735 AF XY: 0.0712 AC XY: 9668 AN XY: 135874

Gnomad AFR exome AF: 0.0427

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.0798

Gnomad EAS exome AF: 0.00984

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.0894

Gnomad NFE exome AF: 0.0707

Gnomad OTH exome AF: 0.0662

GnomAD4 exome AF: 0.0692 AC: 101090 AN: 1461858 Hom.: 3820 Cov.: 32 AF XY: 0.0712 AC XY: 51750 AN XY: 727224

Gnomad4 AFR exome AF: 0.0438

Gnomad4 AMR exome AF: 0.0393

Gnomad4 ASJ exome AF: 0.0799

Gnomad4 EAS exome AF: 0.00788

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.0937

Gnomad4 NFE exome AF: 0.0678

Gnomad4 OTH exome AF: 0.0666

GnomAD4 genome AF: 0.0609 AC: 9263 AN: 152182 Hom.: 325 Cov.: 32 AF XY: 0.0617 AC XY: 4591 AN XY: 74390

Gnomad4 AFR AF: 0.0418

Gnomad4 AMR AF: 0.0459

Gnomad4 ASJ AF: 0.0816

Gnomad4 EAS AF: 0.00714

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.0954

Gnomad4 NFE AF: 0.0694

Gnomad4 OTH AF: 0.0669

Alfa AF: 0.0666 Hom.: 147

Bravo AF: 0.0550

Asia WGS AF: 0.0560 AC: 195 AN: 3478

EpiCase AF: 0.0667

EpiControl AF: 0.0693

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Autosomal dominant cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	10
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs17541505; hg19: chr14-102504838;