7-158869908-G-A

Position:

chr7-158869908-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_StrongPM2PP3_Strong

The NM_018051.5(DYNC2I1):c.69G>A(p.Trp23Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000173 in 1,613,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

DYNC2I1
NM_018051.5 stop_gained, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.63

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 Pathogenic. Variant got 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2I1	NM_018051.5 linkuse as main transcript	c.69G>A	p.Trp23Ter	stop_gained, splice_region_variant	2/25	ENST00000407559.8	NP_060521.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2I1	ENST00000407559.8 linkuse as main transcript	c.69G>A	p.Trp23Ter	stop_gained, splice_region_variant	2/25	1	NM_018051.5	ENSP00000384290	P1
DYNC2I1	ENST00000397143.3 linkuse as main transcript	c.-70G>A		splice_region_variant, 5_prime_UTR_variant	2/3	3		ENSP00000380330

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

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:

0.000337

AC:

AN:

248930

Hom.:

AF XY:

0.000348

AC XY:

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00696

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000974

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000173

AC:

253

AN:

1460986

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

726824

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00677

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.000597

GnomAD4 genome

AF:

0.000171

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000541

Hom.:

Bravo

AF:

0.000193

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000273

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Short-rib thoracic dysplasia 8 with or without polydactyly

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change creates a premature translational stop signal (p.Trp23*) in the WDR60 gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. This variant is present in population databases (rs202111347, gnomAD 0.7%). This variant has not been reported in the literature in individuals affected with WDR60-related conditions. ClinVar contains an entry for this variant (Variation ID: 572127). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_018051.4:c.69G>A in the WDR60 gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. This sequence change creates a premature translational stop signal (p.Trp23*) in the WDR60 gene. Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL and MutationTaster . It is expected to result in an absent or disrupted protein product. Taken together, we interprete this variant as variant of uncertain significance (VUS). ACMG/AMP Criteria applied: PVS1; PP3. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 12, 2018

Variant classified as Uncertain Significance - Favor Benign. The p.Trp23X varian t in WDR60 has not been reported in individuals with short rib-thoracic dysplasi a, but has been identified in 0.7% (69/9846) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD). This nonsense variant leads to a prema ture termination codon at position 23, however, it only occurs in one transcript of the gene (NM_018051.4). This variant also occurs in the last bases of the ex on, which is part of the 5? splice region and computational tools predict altere d splicing. In summary, the clinical significance of the p.Trp23X variant is unc ertain. ACMG/AMP Criteria applied: BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.92

MutationTaster

Benign

1.0

Vest4

0.18

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.67

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.67

Position offset: 0

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