rs116872934

chr11-103283029-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080463.2(DYNC2H1):c.10855G>C(p.Asp3619His) variant causes a missense change. The variant allele was found at a frequency of 0.00671 in 1,602,214 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (59 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.54

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006396532).
• BP6: Variant 11-103283029-G-C is Benign according to our data. Variant chr11-103283029-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 220403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103283029-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00628 (955/152112) while in subpopulation AMR AF= 0.0244 (373/15266). AF 95% confidence interval is 0.0224. There are 8 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.10855G>C	p.Asp3619His	missense_variant	74/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.10834G>C	p.Asp3612His	missense_variant	73/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.10855G>C	p.Asp3619His	missense_variant	74/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.10834G>C	p.Asp3612His	missense_variant	73/89	1	NM_001377.3	P3
	ENST00000649070.1	n.690+9987C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00629 AC: 956 AN: 151994 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00650

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00789 AC: 1918 AN: 243014 Hom.: 22 AF XY: 0.00706 AC XY: 932 AN XY: 131968

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.0295

Gnomad ASJ exome AF: 0.00533

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00251

Gnomad FIN exome AF: 0.00159

Gnomad NFE exome AF: 0.00654

Gnomad OTH exome AF: 0.00716

GnomAD4 exome AF: 0.00675 AC: 9791 AN: 1450102 Hom.: 59 Cov.: 29 AF XY: 0.00660 AC XY: 4753 AN XY: 720410

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.0275

Gnomad4 ASJ exome AF: 0.00556

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00276

Gnomad4 FIN exome AF: 0.00113

Gnomad4 NFE exome AF: 0.00705

Gnomad4 OTH exome AF: 0.00519

GnomAD4 genome AF: 0.00628 AC: 955 AN: 152112 Hom.: 8 Cov.: 32 AF XY: 0.00648 AC XY: 482 AN XY: 74376

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.0244

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00650

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00612 Hom.: 1

Bravo AF: 0.00744

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00137 AC: 5

ESP6500EA AF: 0.00738 AC: 60

ExAC AF: 0.00688 AC: 831

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 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. -

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 02, 2023	- -

Jeune thoracic dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Short rib-polydactyly syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0064	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N;.;.;N
REVEL	Benign	0.26
Sift	Benign	0.041	D;.;.;D
Sift4G	Benign	0.11	T;.;.;T
Polyphen		0.066	B;B;P;P
Vest4		0.57
MVP		0.41
MPC		0.075
ClinPred		0.015	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.38

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: rs116872934; hg19: chr11-103153758; COSMIC: COSV100520203;