Variant rs201521142 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_023036.6(DNAI2):c.284G>A(p.Arg95His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,614,096 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

DNAI2
NM_023036.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.23

Variant links:

Genes affected

DNAI2 (HGNC:18744): (dynein axonemal intermediate chain 2) The protein encoded by this gene belongs to the dynein intermediate chain family, and is part of the dynein complex of respiratory cilia and sperm flagella. Mutations in this gene are associated with primary ciliary dyskinesia type 9. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2010]

DNAI2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI2	NM_023036.6 linkuse as main transcript	c.284G>A	p.Arg95His	missense_variant	3/14	ENST00000311014.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI2	ENST00000311014.11 linkuse as main transcript	c.284G>A	p.Arg95His	missense_variant	3/14	1	NM_023036.6	P2	Q9GZS0-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251434

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

181

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

727246

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:

0.00

Gnomad4 NFE exome

AF:

0.000156

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 07, 2016	The p.R95H variant (also known as c.284G>A), located in coding exon 2 of the DNAI2 gene, results from a G to A substitution at nucleotide position 284. The arginine at codon 95 is replaced by histidine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs201521142. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.02% (2/13006) total alleles studied and 0.02% (2/8600) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 14, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 95 of the DNAI2 protein (p.Arg95His). This variant is present in population databases (rs201521142, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with DNAI2-related conditions. ClinVar contains an entry for this variant (Variation ID: 571240). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	clinical testing	Natera, Inc.	Oct 28, 2019	- -

Primary ciliary dyskinesia 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.98

D;.;D;D

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.79

D;D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Pathogenic

3.7

H;H;H;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.77

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.87

MVP

0.62

MPC

0.97

ClinPred

1.0

GERP RS

5.1

Varity_R

0.80

gMVP

0.52

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