NM_018051.5:c.2305G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_018051.5(DYNC2I1):​c.2305G>A​(p.Glu769Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

DYNC2I1
NM_018051.5 missense

Scores

4
9
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 6.50
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.853
PP5
Variant 7-158926234-G-A is Pathogenic according to our data. Variant chr7-158926234-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446627.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DYNC2I1NM_018051.5 linkc.2305G>A p.Glu769Lys missense_variant Exon 18 of 25 ENST00000407559.8 NP_060521.4 Q8WVS4A0A140VK66

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DYNC2I1ENST00000407559.8 linkc.2305G>A p.Glu769Lys missense_variant Exon 18 of 25 1 NM_018051.5 ENSP00000384290.3 Q8WVS4
DYNC2I1ENST00000444851.5 linkn.1463G>A non_coding_transcript_exon_variant Exon 13 of 20 1 ENSP00000392608.1 H7C022
DYNC2I1ENST00000467220.1 linkn.4104G>A non_coding_transcript_exon_variant Exon 13 of 20 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000403
AC:
10
AN:
248348
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134666
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461360
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
726902
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000151
ExAC
AF:
0.0000331
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:2
-
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jun 01, 2017
Dan Cohn Lab, University Of California Los Angeles
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Asphyxiating thoracic dystrophy 3 Pathogenic:2
-
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jun 01, 2017
Dan Cohn Lab, University Of California Los Angeles
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

See cases Pathogenic:1
Dec 21, 2022
Center for Personalized Medicine, Children's Hospital Los Angeles
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

DYNC2I1-related disorder Pathogenic:1
Dec 18, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The DYNC2I1 c.2305G>A variant is predicted to result in the amino acid substitution p.Glu769Lys. This variant has been reported in the homozygous and compound heterozygous state in two individuals affected with DYNC2I1-related disease (Table S2 ISDR Case # R04-477 and R91-028 in Zhang et al. 2018. PubMed ID: 29068549). At PreventionGenetics, we have observed this variant in the homozygous state in two affected patients. This variant is interpreted as pathogenic or likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/446627/). This variant is reported in 0.029% of alleles in individuals of Latino descent in gnomAD. Based on the available evidence, we classify this variant as likely pathogenic. -

Short-rib thoracic dysplasia 8 with or without polydactyly Uncertain:1
Aug 28, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid with lysine at codon 769 of the WDR60 protein (p.Glu769Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs193204571, ExAC 0.04%). This variant has been observed in individual(s) with short-rib thoracic dysplasia (PMID: 29068549, Invitae). ClinVar contains an entry for this variant (Variation ID: 446627). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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
0.31
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.28
CADD
Uncertain
24
DANN
Benign
0.78
DEOGEN2
Benign
0.016
T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.85
D
MetaSVM
Uncertain
0.28
D
MutationAssessor
Pathogenic
2.9
M
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-2.9
D
REVEL
Uncertain
0.63
Sift
Benign
0.054
T
Sift4G
Uncertain
0.025
D
Polyphen
0.99
D
Vest4
0.84
MVP
0.93
MPC
0.30
ClinPred
0.63
D
GERP RS
5.8
Varity_R
0.39
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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.

Other links and lift over

dbSNP: rs193204571; hg19: chr7-158718925; API