11-103479194-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 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:4
• Conservation: PhyloP100: 8.25

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 Benign. Variant got -9 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 id is 302131.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr11-103479194-G-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 17 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.12886G>C	p.Gly4296Arg	missense_variant	90/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.12865G>C	p.Gly4289Arg	missense_variant	89/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.12886G>C	p.Gly4296Arg	missense_variant	90/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.12865G>C	p.Gly4289Arg	missense_variant	89/89	1	NM_001377.3	P3

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

GnomAD3 exomes AF: 0.0127 AC: 3172 AN: 249120 Hom.: 45 AF XY: 0.0126 AC XY: 1708 AN XY: 135144

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 SAS exome AF: 0.00827

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

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.00798

Gnomad4 ASJ exome AF: 0.0406

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00863

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0136

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

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.00772

Gnomad4 ASJ AF: 0.0381

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00664

Gnomad4 FIN AF: 0.0161

Gnomad4 NFE AF: 0.0156

Gnomad4 OTH AF: 0.0147

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:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Jeune thoracic dystrophy Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Asphyxiating thoracic dystrophy 3 Benign:2

Benign, 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 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2016

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. -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	1.0	D
MetaRNN	Benign	0.0082	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.2	D;N;.;.;D;D
REVEL	Benign	0.24
Sift	Benign	0.14	T;D;.;.;T;D
Sift4G	Benign	0.64	T;D;.;.;T;D
Polyphen		0.047	B;D;B;B;B;.
Vest4		0.62
MutPred		0.46		Gain of solvent accessibility (P = 0.0037);.;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

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: rs144717489; hg19: chr11-103349922; COSMIC: COSV62086990;