rs8010870

Positions:

• chr14-102027424-A-G
• chr14-102027424-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001376.5(DYNC1H1):​c.8928A>G​(p.Leu2976=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,952 control chromosomes in the GnomAD database, including 12,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1916 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10871 hom.)
• Consequence: DYNC1H1 NM_001376.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -3.04

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-102027424-A-G is Benign according to our data. Variant chr14-102027424-A-G is described in ClinVar as [Benign]. Clinvar id is 128944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102027424-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC1H1	NM_001376.5	c.8928A>G	p.Leu2976=	synonymous_variant	46/78	ENST00000360184.10	NP_001367.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.8928A>G	p.Leu2976=	synonymous_variant	46/78	1	NM_001376.5	ENSP00000348965	P1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22609 AN: 151960 Hom.: 1913 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.157

GnomAD3 exomes AF: 0.138 AC: 34676 AN: 251456 Hom.: 2772 AF XY: 0.136 AC XY: 18485 AN XY: 135906

Gnomad AFR exome AF: 0.226

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.253

Gnomad SAS exome AF: 0.171

Gnomad FIN exome AF: 0.0952

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.116 AC: 169840 AN: 1461874 Hom.: 10871 Cov.: 33 AF XY: 0.117 AC XY: 85244 AN XY: 727240

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.236

Gnomad4 SAS exome AF: 0.173

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.126

GnomAD4 genome AF: 0.149 AC: 22632 AN: 152078 Hom.: 1916 Cov.: 32 AF XY: 0.148 AC XY: 10994 AN XY: 74380

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.238

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.156

Alfa AF: 0.125 Hom.: 738

Bravo AF: 0.155

Asia WGS AF: 0.202 AC: 703 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.110

ClinVar

Significance: Benign

Submissions summary: Benign:16

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	-	- -
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	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 -
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	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Charcot-Marie-Tooth disease axonal type 2O Benign:3

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 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	Genome-Nilou Lab	Jul 30, 2021	- -

Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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 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. -

Intellectual disability, autosomal dominant 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.40
DANN	Benign	0.48
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: rs8010870; hg19: chr14-102493761; COSMIC: COSV64135556; COSMIC: COSV64135556;