rs17541179

Positions:

• chr14-102016399-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001376.5(DYNC1H1):​c.7524A>G​(p.Leu2508=) variant causes a synonymous change. The variant allele was found at a frequency of 0.012 in 1,614,176 control chromosomes in the GnomAD database, including 434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (143 hom., cov: 33)
  • Exomes 𝑓: 0.010 (291 hom.)
• Consequence: DYNC1H1 NM_001376.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.38

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 14-102016399-A-G is Benign according to our data. Variant chr14-102016399-A-G is described in ClinVar as [Benign]. Clinvar id is 128942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102016399-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC1H1	NM_001376.5	c.7524A>G	p.Leu2508=	synonymous_variant	37/78	ENST00000360184.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.7524A>G	p.Leu2508=	synonymous_variant	37/78	1	NM_001376.5	P1

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4431 AN: 152174 Hom.: 142 Cov.: 33

Gnomad AFR AF: 0.0849

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.0165 AC: 4145 AN: 251490 Hom.: 105 AF XY: 0.0165 AC XY: 2238 AN XY: 135916

Gnomad AFR exome AF: 0.0890

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0395

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00624

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.0102 AC: 14969 AN: 1461886 Hom.: 291 Cov.: 31 AF XY: 0.0110 AC XY: 8017 AN XY: 727246

Gnomad4 AFR exome AF: 0.0894

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.0288

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0382

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00559

Gnomad4 OTH exome AF: 0.0153

GnomAD4 genome AF: 0.0291 AC: 4437 AN: 152290 Hom.: 143 Cov.: 33 AF XY: 0.0286 AC XY: 2129 AN XY: 74460

Gnomad4 AFR AF: 0.0848

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.0262

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0336

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00544

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0179 Hom.: 26

Bravo AF: 0.0318

Asia WGS AF: 0.0230 AC: 78 AN: 3478

EpiCase AF: 0.00829

EpiControl AF: 0.00836

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

Mar 17, 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

clinical testing

GeneDx

Mar 03, 2015

- -

Autosomal dominant cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.53
CADD	Benign	12
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs17541179; hg19: chr14-102482736; COSMIC: COSV64137017; COSMIC: COSV64137017;