rs73167274

Positions:

chr7-158934539-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000407559.8(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
ENST00000407559.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 541526.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2I1	NM_018051.5 linkuse as main transcript	c.2768C>A	p.Pro923Gln	missense_variant	23/25	ENST00000407559.8	NP_060521.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DYNC2I1	ENST00000407559.8 linkuse as main transcript	c.2768C>A	p.Pro923Gln	missense_variant	23/25	1	NM_018051.5	ENSP00000384290	P1
DYNC2I1	ENST00000444851.5 linkuse as main transcript	c.*357C>A		3_prime_UTR_variant, NMD_transcript_variant	18/20	1		ENSP00000392608
DYNC2I1	ENST00000467220.1 linkuse as main transcript	n.4567C>A		non_coding_transcript_exon_variant	18/20	2
DYNC2I1	ENST00000454771.1 linkuse as main transcript	c.158C>A	p.Pro53Gln	missense_variant, NMD_transcript_variant	2/5	4		ENSP00000399971

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

GnomAD3 exomes

AF:

0.00251

AC:

399

AN:

158718

Hom.:

AF XY:

0.00220

AC XY:

183

AN XY:

83214

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 SAS exome

AF:

0.000135

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

Gnomad4 AFR exome

AF:

0.000443

Gnomad4 AMR exome

AF:

0.00314

Gnomad4 ASJ exome

AF:

0.000199

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000889

Gnomad4 FIN exome

AF:

0.00441

Gnomad4 NFE exome

AF:

0.00333

Gnomad4 OTH exome

AF:

0.00291

GnomAD4 genome

AF:

0.00262

AC:

398

AN:

152188

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

205

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00236

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00690

Gnomad4 NFE

AF:

0.00350

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00299

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2022

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

MutationTaster

Benign

0.94

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over