GeneBe

7-158911554-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_018051.5(DYNC2I1):​c.1465C>T​(p.Arg489*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DYNC2I1
NM_018051.5 stop_gained

Scores

2
3
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.79

Publications

3 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DYNC2I1NM_018051.5 linkc.1465C>T p.Arg489* stop_gained Exon 12 of 25 ENST00000407559.8 NP_060521.4 Q8WVS4A0A140VK66

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DYNC2I1ENST00000407559.8 linkc.1465C>T p.Arg489* stop_gained Exon 12 of 25 1 NM_018051.5 ENSP00000384290.3 Q8WVS4
DYNC2I1ENST00000444851.5 linkn.796C>T non_coding_transcript_exon_variant Exon 8 of 20 1 ENSP00000392608.1 H7C022
DYNC2I1ENST00000467220.1 linkn.3264C>T non_coding_transcript_exon_variant Exon 7 of 20 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459708
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
725992
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33388
American (AMR)
AF:
0.00
AC:
0
AN:
44352
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26090
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39654
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85592
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53352
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111222
Other (OTH)
AF:
0.00
AC:
0
AN:
60292
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Uncertain
0.42
Eigen_PC
Benign
0.22
FATHMM_MKL
Uncertain
0.84
D
PhyloP100
2.8
Vest4
0.34
GERP RS
1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=13/187
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs116193143; hg19: chr7-158704245; API