chr9-128633790-C-T

Position:

chr9-128633790-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_052844.4(DYNC2I2):c.1565G>A(p.Arg522Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,613,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R522G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

DYNC2I2
NM_052844.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.35

Variant links:

Genes affected

DYNC2I2 (HGNC:28296): (dynein 2 intermediate chain 2) 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), which may facilitate 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. Defects in this gene are a cause of short-rib thoracic dysplasia 11 with or without polydactyly. [provided by RefSeq, Mar 2014]

DYNC2I2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29954785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DYNC2I2	NM_052844.4 linkuse as main transcript	c.1565G>A	p.Arg522Gln	missense_variant	9/9	ENST00000372715.7
DYNC2I2	XM_047424057.1 linkuse as main transcript	c.1565G>A	p.Arg522Gln	missense_variant	10/10
DYNC2I2	XM_011519179.3 linkuse as main transcript	c.1481G>A	p.Arg494Gln	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2I2	ENST00000372715.7 linkuse as main transcript	c.1565G>A	p.Arg522Gln	missense_variant	9/9	1	NM_052844.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

250968

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000794

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000117

AC:

171

AN:

1461248

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

726942

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000127

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Short-rib thoracic dysplasia 11 with or without polydactyly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 04, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 522 of the WDR34 protein (p.Arg522Gln). This variant is present in population databases (rs373418441, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with WDR34-related conditions. ClinVar contains an entry for this variant (Variation ID: 936974). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

Eigen

Benign

-0.040

Eigen_PC

Benign

0.029

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.053

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

0.99

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.8

REVEL

Benign

0.17

Sift

Benign

0.069

Sift4G

Benign

0.081

Polyphen

0.31

Vest4

0.48

MVP

0.37

MPC

0.14

ClinPred

0.15

GERP RS

4.5

Varity_R

0.14

gMVP

0.36

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

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