rs589623

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001377.3(DYNC2H1):​c.8612G>A​(p.Arg2871Gln) variant causes a missense change. The variant allele was found at a frequency of 0.793 in 1,521,494 control chromosomes in the GnomAD database, including 480,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 43913 hom., cov: 32)
Exomes 𝑓: 0.80 ( 436169 hom. )

Consequence

DYNC2H1
NM_001377.3 missense

Scores

4
14

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.41
Variant links:
Genes affected
DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=2.285225E-6).
BP6
Variant 11-103211861-G-A is Benign according to our data. Variant chr11-103211861-G-A is described in ClinVar as [Benign]. Clinvar id is 302073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103211861-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DYNC2H1NM_001080463.2 linkc.8612G>A p.Arg2871Gln missense_variant Exon 54 of 90 ENST00000650373.2 NP_001073932.1 Q8NCM8-2
DYNC2H1NM_001377.3 linkc.8612G>A p.Arg2871Gln missense_variant Exon 54 of 89 ENST00000375735.7 NP_001368.2 Q8NCM8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DYNC2H1ENST00000650373.2 linkc.8612G>A p.Arg2871Gln missense_variant Exon 54 of 90 NM_001080463.2 ENSP00000497174.1 Q8NCM8-2
DYNC2H1ENST00000375735.7 linkc.8612G>A p.Arg2871Gln missense_variant Exon 54 of 89 1 NM_001377.3 ENSP00000364887.2 Q8NCM8-1
DYNC2H1ENST00000334267.11 linkc.2205+77442G>A intron_variant Intron 15 of 19 1 ENSP00000334021.7 Q8NCM8-3
DYNC2H1ENST00000533027.1 linkn.212G>A non_coding_transcript_exon_variant Exon 3 of 4 3

Frequencies

GnomAD3 genomes
AF:
0.756
AC:
114756
AN:
151872
Hom.:
43869
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.621
Gnomad AMI
AF:
0.899
Gnomad AMR
AF:
0.835
Gnomad ASJ
AF:
0.846
Gnomad EAS
AF:
0.777
Gnomad SAS
AF:
0.772
Gnomad FIN
AF:
0.790
Gnomad MID
AF:
0.778
Gnomad NFE
AF:
0.804
Gnomad OTH
AF:
0.779
GnomAD3 exomes
AF:
0.794
AC:
120667
AN:
152026
Hom.:
48240
AF XY:
0.795
AC XY:
63767
AN XY:
80228
show subpopulations
Gnomad AFR exome
AF:
0.603
Gnomad AMR exome
AF:
0.848
Gnomad ASJ exome
AF:
0.839
Gnomad EAS exome
AF:
0.767
Gnomad SAS exome
AF:
0.765
Gnomad FIN exome
AF:
0.802
Gnomad NFE exome
AF:
0.805
Gnomad OTH exome
AF:
0.806
GnomAD4 exome
AF:
0.797
AC:
1091217
AN:
1369504
Hom.:
436169
Cov.:
32
AF XY:
0.796
AC XY:
537112
AN XY:
674624
show subpopulations
Gnomad4 AFR exome
AF:
0.610
Gnomad4 AMR exome
AF:
0.847
Gnomad4 ASJ exome
AF:
0.848
Gnomad4 EAS exome
AF:
0.731
Gnomad4 SAS exome
AF:
0.766
Gnomad4 FIN exome
AF:
0.802
Gnomad4 NFE exome
AF:
0.804
Gnomad4 OTH exome
AF:
0.787
GnomAD4 genome
AF:
0.756
AC:
114855
AN:
151990
Hom.:
43913
Cov.:
32
AF XY:
0.756
AC XY:
56184
AN XY:
74278
show subpopulations
Gnomad4 AFR
AF:
0.621
Gnomad4 AMR
AF:
0.835
Gnomad4 ASJ
AF:
0.846
Gnomad4 EAS
AF:
0.777
Gnomad4 SAS
AF:
0.774
Gnomad4 FIN
AF:
0.790
Gnomad4 NFE
AF:
0.804
Gnomad4 OTH
AF:
0.779
Alfa
AF:
0.799
Hom.:
101576
Bravo
AF:
0.754
TwinsUK
AF:
0.803
AC:
2979
ALSPAC
AF:
0.804
AC:
3099
ESP6500AA
AF:
0.630
AC:
2258
ESP6500EA
AF:
0.810
AC:
6501
ExAC
AF:
0.741
AC:
70849
Asia WGS
AF:
0.734
AC:
2544
AN:
3462

ClinVar

Significance: Benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 03, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 28, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Asphyxiating thoracic dystrophy 3 Benign:3
May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 30, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Jeune thoracic dystrophy Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Short rib-polydactyly syndrome Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.093
T;T;.;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.81
.;T;.;T
MetaRNN
Benign
0.0000023
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.61
N;N;N;N
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.7
N;.;.;N
REVEL
Benign
0.099
Sift
Benign
0.23
T;.;.;T
Sift4G
Benign
0.30
T;.;.;T
Polyphen
0.72
P;P;B;B
Vest4
0.049
MPC
0.084
ClinPred
0.017
T
GERP RS
5.8
Varity_R
0.17
gMVP
0.15

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.

Other links and lift over

dbSNP: rs589623; hg19: chr11-103082590; COSMIC: COSV62088525; API