rs73167274

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018051.5(DYNC2I1):c.2768C>A(p.Pro923Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,551,660 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P923S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 13 hom. )

Consequence

DYNC2I1
NM_018051.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.17

Publications

4 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005575031).

BP6

Variant 7-158934539-C-A is Benign according to our data. Variant chr7-158934539-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541526.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00262 (398/152188) while in subpopulation NFE AF = 0.0035 (238/67996). AF 95% confidence interval is 0.00314. There are 1 homozygotes in GnomAd4. There are 205 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2I1	NM_018051.5 link	c.2768C>A	p.Pro923Gln	missense_variant	Exon 23 of 25	ENST00000407559.8	NP_060521.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2I1	ENST00000407559.8 link	c.2768C>A	p.Pro923Gln	missense_variant	Exon 23 of 25	1	NM_018051.5	ENSP00000384290.3

Frequencies

GnomAD3 genomes

AF:

0.00262

AC:

398

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00690

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00350

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00251

AC:

399

AN:

158718

AF XY:

0.00220

show subpopulations

Gnomad AFR exome

AF:

0.000832

Gnomad AMR exome

AF:

0.00287

Gnomad ASJ exome

AF:

0.000351

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00523

Gnomad NFE exome

AF:

0.00342

Gnomad OTH exome

AF:

0.00290

GnomAD4 exome

AF:

0.00295

AC:

4126

AN:

1399472

Hom.:

Cov.:

AF XY:

0.00288

AC XY:

1985

AN XY:

690246

show subpopulations

African (AFR)

AF:

0.000443

AC:

AN:

31616

American (AMR)

AF:

0.00314

AC:

111

AN:

35382

Ashkenazi Jewish (ASJ)

AF:

0.000199

AC:

AN:

25128

East Asian (EAS)

AF:

0.00

AC:

AN:

35920

South Asian (SAS)

AF:

0.0000889

AC:

AN:

78728

European-Finnish (FIN)

AF:

0.00441

AC:

219

AN:

49648

Middle Eastern (MID)

AF:

0.00211

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00333

AC:

3589

AN:

1079250

Other (OTH)

AF:

0.00291

AC:

169

AN:

58110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

190

380

570

760

950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00262

AC:

398

AN:

152188

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

205

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41528

American (AMR)

AF:

0.00236

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00690

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00350

AC:

238

AN:

67996

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00223

Hom.:

Bravo

AF:

0.00238

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00110

AC:

ESP6500EA

AF:

0.00359

AC:

ExAC

AF:

0.00124

AC:

125

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2768C>A (p.P923Q) alteration is located in exon 23 (coding exon 23) of the WDR60 gene. This alteration results from a C to A substitution at nucleotide position 2768, causing the proline (P) at amino acid position 923 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

DYNC2I1-related disorder

Benign:1

Oct 22, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Short-rib thoracic dysplasia 8 with or without polydactyly

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.036

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0092

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

PhyloP100

3.2

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.9

REVEL

Benign

0.12

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.027

Polyphen

1.0

Vest4

0.29

MVP

0.59

MPC

0.43

ClinPred

0.054

GERP RS

5.8

Varity_R

0.30

gMVP

0.35

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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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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