rs17099969

chr11-103121378-G-Achr11-103121378-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080463.2(DYNC2H1):c.1367G>A(p.Arg456Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,598,844 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (149 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (138 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.76

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001755178).
• BP6: Variant 11-103121378-G-A is Benign according to our data. Variant chr11-103121378-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 302013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103121378-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.1367G>A	p.Arg456Gln	missense_variant	10/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.1367G>A	p.Arg456Gln	missense_variant	10/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.1367G>A	p.Arg456Gln	missense_variant	10/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.1367G>A	p.Arg456Gln	missense_variant	10/89	1	NM_001377.3	P3

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3468 AN: 152026 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.0790

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0211

GnomAD3 exomes AF: 0.00562 AC: 1297 AN: 230702 Hom.: 52 AF XY: 0.00429 AC XY: 536 AN XY: 125048

Gnomad AFR exome AF: 0.0779

Gnomad AMR exome AF: 0.00372

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000376

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000104

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00236 AC: 3408 AN: 1446700 Hom.: 138 Cov.: 30 AF XY: 0.00203 AC XY: 1458 AN XY: 718950

Gnomad4 AFR exome AF: 0.0859

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.0000782

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.0000970

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000795

Gnomad4 OTH exome AF: 0.00542

GnomAD4 genome AF: 0.0228 AC: 3471 AN: 152144 Hom.: 149 Cov.: 32 AF XY: 0.0217 AC XY: 1617 AN XY: 74372

Gnomad4 AFR AF: 0.0788

Gnomad4 AMR AF: 0.00857

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.00318 Hom.: 39

Bravo AF: 0.0262

ESP6500AA AF: 0.0760 AC: 274

ESP6500EA AF: 0.000491 AC: 4

ExAC AF: 0.00627 AC: 757

Asia WGS AF: 0.00347 AC: 12 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Jeune thoracic dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, 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 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 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 28, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 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	0.071
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	16
Dann	Uncertain	0.98
Eigen	Benign	-0.13
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T;.;T;T;.;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.67	D;D;D
PrimateAI	Benign	0.26	T
Polyphen		0.0010, 0.20, 0.0	.;B;B;B;B;B
Vest4		0.13, 0.14, 0.12
MVP		0.58
MPC		0.070
ClinPred		0.0076	T
GERP RS		5.4
Varity_R		0.033
gMVP		0.20

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: rs17099969; hg19: chr11-102992107; COSMIC: COSV62101597;