rs150887098

chr11-103176255-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001080463.2(DYNC2H1):c.5695G>A(p.Val1899Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000552 in 1,517,200 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (2 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 6.45

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010181516).
• BP6: Variant 11-103176255-G-A is Benign according to our data. Variant chr11-103176255-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167010.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Benign=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.5695G>A	p.Val1899Ile	missense_variant	37/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.5695G>A	p.Val1899Ile	missense_variant	37/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.5695G>A	p.Val1899Ile	missense_variant	37/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.5695G>A	p.Val1899Ile	missense_variant	37/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+41836G>A		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*3240G>A		3_prime_UTR_variant, NMD_transcript_variant	35/51

Frequencies

GnomAD3 genomes AF: 0.000868 AC: 132 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000863 AC: 112 AN: 129822 Hom.: 1 AF XY: 0.000816 AC XY: 56 AN XY: 68598

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000901

Gnomad ASJ exome AF: 0.00564

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000626

Gnomad OTH exome AF: 0.00308

GnomAD4 exome AF: 0.000516 AC: 705 AN: 1365020 Hom.: 2 Cov.: 28 AF XY: 0.000548 AC XY: 368 AN XY: 671520

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00126

Gnomad4 ASJ exome AF: 0.00509

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000379

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.000867 AC: 132 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000955 AC XY: 71 AN XY: 74374

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000875 Hom.: 0

Bravo AF: 0.00117

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000760 AC: 6

ExAC AF: 0.000361 AC: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Uncertain:3

Uncertain significance, 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, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2017	- -

Jeune thoracic dystrophy Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 17, 2019

- -

DYNC2H1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 14, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	23
Dann	Benign	0.88
DEOGEN2	Benign	0.096	T;T;.;.
Eigen	Benign	-0.056
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.1	L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.42	N;.;.;N
REVEL	Uncertain	0.32
Sift	Benign	0.69	T;.;.;T
Sift4G	Benign	0.61	T;.;.;T
Polyphen		0.029	B;B;B;B
Vest4		0.17
MVP		0.64
MPC		0.058
ClinPred		0.014	T
GERP RS		4.6
Varity_R		0.086
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150887098; hg19: chr11-103046984;