rs17301028

Variant names:

• chr11-103109595-C-T
• rs17301028
• NM_001080463.2:c.21C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001080463.2(DYNC2H1):​c.21C>T​(p.Asp7Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.087 in 1,613,576 control chromosomes in the GnomAD database, including 7,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (436 hom., cov: 32)
  • Exomes 𝑓: 0.089 (6608 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.28
• Publications: 14 publications found

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

DYNC2H1 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 11-103109595-C-T is Benign according to our data. Variant chr11-103109595-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 301995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.21C>T	p.Asp7Asp	synonymous_variant	Exon 1 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.21C>T	p.Asp7Asp	synonymous_variant	Exon 1 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.21C>T	p.Asp7Asp	synonymous_variant	Exon 1 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.21C>T	p.Asp7Asp	synonymous_variant	Exon 1 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes AF: 0.0654 AC: 9955 AN: 152128 Hom.: 435 Cov.: 32

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0709

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0849

Gnomad FIN AF: 0.0459

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0951

Gnomad OTH AF: 0.0753

GnomAD2 exomes AF: 0.0736 AC: 18308 AN: 248748 AF XY: 0.0776

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.0484

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.0444

Gnomad NFE exome AF: 0.0960

Gnomad OTH exome AF: 0.0833

GnomAD4 exome AF: 0.0892 AC: 130393 AN: 1461330 Hom.: 6608 Cov.: 31 AF XY: 0.0897 AC XY: 65213 AN XY: 726904

African (AFR) AF: 0.0138 AC: 463 AN: 33480

American (AMR) AF: 0.0520 AC: 2326 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3571 AN: 26128

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39696

South Asian (SAS) AF: 0.0944 AC: 8139 AN: 86208

European-Finnish (FIN) AF: 0.0455 AC: 2429 AN: 53370

Middle Eastern (MID) AF: 0.127 AC: 733 AN: 5766

European-Non Finnish (NFE) AF: 0.0967 AC: 107514 AN: 1111612

Other (OTH) AF: 0.0863 AC: 5209 AN: 60366

GnomAD4 genome AF: 0.0654 AC: 9958 AN: 152246 Hom.: 436 Cov.: 32 AF XY: 0.0636 AC XY: 4735 AN XY: 74440

African (AFR) AF: 0.0191 AC: 792 AN: 41560

American (AMR) AF: 0.0709 AC: 1083 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 472 AN: 3468

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0858 AC: 414 AN: 4826

European-Finnish (FIN) AF: 0.0459 AC: 487 AN: 10602

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0951 AC: 6469 AN: 68006

Other (OTH) AF: 0.0745 AC: 157 AN: 2106

Alfa AF: 0.0876 Hom.: 1102

Bravo AF: 0.0634

Asia WGS AF: 0.0280 AC: 100 AN: 3478

EpiCase AF: 0.0970

EpiControl AF: 0.102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 2016

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

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jeune thoracic dystrophy Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Asphyxiating thoracic dystrophy 3 Benign:1

Jan 13, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		2.3
PromoterAI		0.0064	Neutral
Mutation Taster		=100/0	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: rs17301028; hg19: chr11-102980324; COSMIC: COSV107392413;