chr11-103153376-G-A

Position:

• chr11-103153376-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001377.3(DYNC2H1):​c.3170G>A​(p.Arg1057His) variant causes a missense change. The variant allele was found at a frequency of 0.000884 in 1,550,724 control chromosomes in the GnomAD database, including 1 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 0.00069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (1 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 5.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017768025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.3170G>A	p.Arg1057His	missense_variant	22/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.3170G>A	p.Arg1057His	missense_variant	22/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.3170G>A	p.Arg1057His	missense_variant	22/90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.3170G>A	p.Arg1057His	missense_variant	22/89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes AF: 0.000691 AC: 105 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000506 AC: 80 AN: 158136 Hom.: 0 AF XY: 0.000540 AC XY: 45 AN XY: 83320

Gnomad AFR exome AF: 0.000117

Gnomad AMR exome AF: 0.000775

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000618

Gnomad NFE exome AF: 0.000880

Gnomad OTH exome AF: 0.000904

GnomAD4 exome AF: 0.000905 AC: 1266 AN: 1398546 Hom.: 1 Cov.: 30 AF XY: 0.000854 AC XY: 589 AN XY: 689716

Gnomad4 AFR exome AF: 0.000284

Gnomad4 AMR exome AF: 0.00115

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000182

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.000655

GnomAD4 genome AF: 0.000690 AC: 105 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74404

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000979 Hom.: 0

Bravo AF: 0.000895

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000623 AC: 5

ExAC AF: 0.000371 AC: 41

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Asphyxiating thoracic dystrophy 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	The DYNC2H1 c.3170G>A; p.Arg1057His variant (rs191381310), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 281379). This variant is found in the general population with an overall allele frequency of 0.05% (99/189,496 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.126). Due to limited information, the clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jeune thoracic dystrophy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;D;D;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;.;D;.;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.018	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	.;M;M;M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.8	.;D;.;.;D
REVEL	Benign	0.13
Sift	Uncertain	0.018	.;D;.;.;D
Sift4G	Benign	0.068	.;T;.;.;T
Polyphen		0.52, 0.65	.;P;P;P;P
Vest4		0.23, 0.21
MVP		0.59
MPC		0.15
ClinPred		0.055	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.46

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: rs191381310; hg19: chr11-103024105; COSMIC: COSV100520243;