11-103479194-G-C

Variant names:

• chr11-103479194-G-C
• rs144717489
• NM_001080463.2:c.12886G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001080463.2(DYNC2H1):​c.12886G>C​(p.Gly4296Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,766 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.014 (189 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 8.25
• Publications: 10 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0082240105).
• BP6: Variant 11-103479194-G-C is Benign according to our data. Variant chr11-103479194-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 302131.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0108 (1649/152160) while in subpopulation NFE AF = 0.0156 (1060/67986). AF 95% confidence interval is 0.0148. There are 17 homozygotes in GnomAd4. There are 795 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080463.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.12886G>C	p.Gly4296Arg	missense	Exon 90 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.12865G>C	p.Gly4289Arg	missense	Exon 89 of 89	NP_001368.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.12886G>C	p.Gly4296Arg	missense	Exon 90 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.12865G>C	p.Gly4289Arg	missense	Exon 89 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2704G>C	p.Gly902Arg	missense	Exon 20 of 20	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1647 AN: 152042 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00242

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.0381

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0127 AC: 3172 AN: 249120 AF XY: 0.0126

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00744

Gnomad ASJ exome AF: 0.0385

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0151

GnomAD4 exome AF: 0.0137 AC: 20055 AN: 1461606 Hom.: 189 Cov.: 30 AF XY: 0.0137 AC XY: 9967 AN XY: 727088

African (AFR) AF: 0.00233 AC: 78 AN: 33480

American (AMR) AF: 0.00798 AC: 357 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 1062 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00863 AC: 744 AN: 86252

European-Finnish (FIN) AF: 0.0176 AC: 938 AN: 53394

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5768

European-Non Finnish (NFE) AF: 0.0144 AC: 15997 AN: 1111814

Other (OTH) AF: 0.0136 AC: 819 AN: 60366

GnomAD4 genome AF: 0.0108 AC: 1649 AN: 152160 Hom.: 17 Cov.: 32 AF XY: 0.0107 AC XY: 795 AN XY: 74360

African (AFR) AF: 0.00241 AC: 100 AN: 41516

American (AMR) AF: 0.00772 AC: 118 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0381 AC: 132 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4818

European-Finnish (FIN) AF: 0.0161 AC: 171 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0156 AC: 1060 AN: 67986

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0164 Hom.: 21

Bravo AF: 0.0105

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.00204 AC: 8

ESP6500EA AF: 0.0161 AC: 134

ExAC AF: 0.0129 AC: 1557

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0159

EpiControl AF: 0.0155

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Jeune thoracic dystrophy Uncertain:1 Benign:1

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: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asphyxiating thoracic dystrophy 3 Benign:2

Aug 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not specified Benign:1

Jun 29, 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.

not provided Benign:1

Oct 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DYNC2H1: BS1, BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.24
Sift	Benign	0.14	T
Sift4G	Benign	0.64	T
Polyphen		0.047	B
Vest4		0.62
MutPred		0.46		Gain of solvent accessibility (P = 0.0037)
MPC		0.094
ClinPred		0.048	T
GERP RS		4.9
Varity_R		0.56
gMVP		0.65
Mutation Taster		=59/41	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: rs144717489; hg19: chr11-103349922; COSMIC: COSV62086990;