NM_001080463.2:c.5558+4A>G

Variant names:

• chr11-103173309-A-G
• rs11225578
• NM_001080463.2:c.5558+4A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001080463.2(DYNC2H1):​c.5558+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,522,134 control chromosomes in the GnomAD database, including 11,089 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (848 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10241 hom.)
• Consequence: DYNC2H1 NM_001080463.2 splice_region, intron
• Scores: Splicing: ADA: 0.9919
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.70
• Publications: 12 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-103173309-A-G is Benign according to our data. Variant chr11-103173309-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.5558+4A>G		splice_region_variant, intron_variant	Intron 35 of 89	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.5558+4A>G		splice_region_variant, intron_variant	Intron 35 of 88	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.5558+4A>G		splice_region_variant, intron_variant	Intron 35 of 89		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.5558+4A>G		splice_region_variant, intron_variant	Intron 35 of 88	1	NM_001377.3	ENSP00000364887.2
DYNC2H1	ENST00000334267.11	c.2205+38890A>G		intron_variant	Intron 15 of 19	1		ENSP00000334021.7
DYNC2H1	ENST00000649323.1	n.*3103+4A>G		splice_region_variant, intron_variant	Intron 33 of 50			ENSP00000497581.1

Frequencies

GnomAD3 genomes AF: 0.0950 AC: 14411 AN: 151754 Hom.: 844 Cov.: 32

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0815

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0896

GnomAD2 exomes AF: 0.115 AC: 20486 AN: 177376 AF XY: 0.119

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.0493

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.249

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.117 AC: 160450 AN: 1370262 Hom.: 10241 Cov.: 26 AF XY: 0.118 AC XY: 79995 AN XY: 679518

African (AFR) AF: 0.0322 AC: 912 AN: 28308

American (AMR) AF: 0.0508 AC: 1522 AN: 29978

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2773 AN: 24012

East Asian (EAS) AF: 0.230 AC: 7858 AN: 34114

South Asian (SAS) AF: 0.142 AC: 9807 AN: 69152

European-Finnish (FIN) AF: 0.115 AC: 5969 AN: 51824

Middle Eastern (MID) AF: 0.123 AC: 656 AN: 5346

European-Non Finnish (NFE) AF: 0.116 AC: 124229 AN: 1070976

Other (OTH) AF: 0.119 AC: 6724 AN: 56552

GnomAD4 genome AF: 0.0950 AC: 14421 AN: 151872 Hom.: 848 Cov.: 32 AF XY: 0.0958 AC XY: 7110 AN XY: 74222

African (AFR) AF: 0.0381 AC: 1581 AN: 41484

American (AMR) AF: 0.0813 AC: 1241 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3470

East Asian (EAS) AF: 0.251 AC: 1295 AN: 5164

South Asian (SAS) AF: 0.152 AC: 729 AN: 4802

European-Finnish (FIN) AF: 0.111 AC: 1174 AN: 10536

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7676 AN: 67846

Other (OTH) AF: 0.0968 AC: 204 AN: 2108

Alfa AF: 0.110 Hom.: 534

Bravo AF: 0.0890

Asia WGS AF: 0.203 AC: 705 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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 -

May 06, 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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Benign	0.87
PhyloP100		2.7
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.65
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

Other links and lift over

dbSNP: rs11225578; hg19: chr11-103044038; COSMIC: COSV62101811;