rs139730326

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018051.5(DYNC2I1):c.941C>T(p.Ala314Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,613,532 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0097 ( 16 hom., cov: 32)

Exomes 𝑓: 0.011 ( 97 hom. )

Consequence

DYNC2I1
NM_018051.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0930

Publications

10 publications found

Variant links:

Genes affected

DYNC2I1 (HGNC:21862): (dynein 2 intermediate chain 1) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD) and may facilitate the formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes including cell cycle progression, signal transduction, apoptosis, and gene regulation. The encoded protein contains four WD repeats and may play a role in the formation of cilia. Mutations in this gene have been associated with short-rib polydactyly and Jeune syndromes. [provided by RefSeq, Mar 2014]

DYNC2I1 Gene-Disease associations (from GenCC):

short-rib thoracic dysplasia 8 with or without polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short rib-polydactyly syndrome, Verma-Naumoff type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYNC2I1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032497942).

BP6

Variant 7-158887026-C-T is Benign according to our data. Variant chr7-158887026-C-T is described in ClinVar as [Benign]. Clinvar id is 474633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00971 (1479/152240) while in subpopulation NFE AF = 0.0146 (992/68022). AF 95% confidence interval is 0.0138. There are 16 homozygotes in GnomAd4. There are 685 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2I1	NM_018051.5 link	c.941C>T	p.Ala314Val	missense_variant	Exon 7 of 25	ENST00000407559.8	NP_060521.4	Q8WVS4A0A140VK66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DYNC2I1	ENST00000407559.8 link	c.941C>T	p.Ala314Val	missense_variant	Exon 7 of 25	1	NM_018051.5	ENSP00000384290.3	Q8WVS4
DYNC2I1	ENST00000444851.5 link	n.272C>T		non_coding_transcript_exon_variant	Exon 3 of 20	1		ENSP00000392608.1	H7C022
DYNC2I1	ENST00000467220.1 link	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 20	2

Frequencies

GnomAD3 genomes

AF:

0.00972

AC:

1478

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.00897

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00746

Gnomad FIN

AF:

0.00707

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00981

AC:

2444

AN:

249074

AF XY:

0.0106

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00739

Gnomad ASJ exome

AF:

0.0139

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00617

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.0108

AC:

15750

AN:

1461292

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

7974

AN XY:

726962

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

33478

American (AMR)

AF:

0.00725

AC:

324

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0132

AC:

345

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39682

South Asian (SAS)

AF:

0.00596

AC:

514

AN:

86228

European-Finnish (FIN)

AF:

0.00620

AC:

331

AN:

53392

Middle Eastern (MID)

AF:

0.0219

AC:

126

AN:

5762

European-Non Finnish (NFE)

AF:

0.0121

AC:

13447

AN:

1111544

Other (OTH)

AF:

0.0101

AC:

607

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

762

1524

2286

3048

3810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00971

AC:

1479

AN:

152240

Hom.:

Cov.:

AF XY:

0.00920

AC XY:

685

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00222

AC:

AN:

41514

American (AMR)

AF:

0.00896

AC:

137

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00746

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00707

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

992

AN:

68022

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

162

244

325

406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0128

Hom.:

Bravo

AF:

0.00946

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00217

AC:

ESP6500EA

AF:

0.0128

AC:

105

ExAC

AF:

0.0100

AC:

1212

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0160

EpiControl

AF:

0.0160

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DYNC2I1: BP4, BS1, BS2 -

Short-rib thoracic dysplasia 8 with or without polydactyly

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0021

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0032

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

PhyloP100

-0.093

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.79

REVEL

Benign

0.0070

Sift

Benign

0.038

Sift4G

Benign

0.32

Polyphen

0.13

Vest4

0.18

MPC

0.19

ClinPred

0.0012

GERP RS

1.4

Varity_R

0.029

gMVP

0.051

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs139730326

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over