rs1979370

Positions:

chr17-74312180-G-A

Variant summary

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

The NM_023036.6(DNAI2):c.1672G>A(p.Ala558Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,610,478 control chromosomes in the GnomAD database, including 631,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 48710 hom., cov: 27)

Exomes 𝑓: 0.89 ( 582883 hom. )

Consequence

DNAI2
NM_023036.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.17

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:

DNAI2 (HGNC:):

DNAI2 links:

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=6.3897465E-7).

BP6

Variant 17-74312180-G-A is Benign according to our data. Variant chr17-74312180-G-A is described in ClinVar as [Benign]. Clinvar id is 163171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-74312180-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI2	NM_023036.6 linkuse as main transcript	c.1672G>A	p.Ala558Thr	missense_variant	12/14	ENST00000311014.11	NP_075462.3	Q9GZS0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI2	ENST00000311014.11 linkuse as main transcript	c.1672G>A	p.Ala558Thr	missense_variant	12/14	1	NM_023036.6	ENSP00000308312.6		Q9GZS0-1

Frequencies

GnomAD3 genomes

AF:

0.782

AC:

118272

AN:

151280

Hom.:

48707

Cov.:

show subpopulations

Gnomad AFR

AF:

0.491

Gnomad AMI

AF:

0.881

Gnomad AMR

AF:

0.883

Gnomad ASJ

AF:

0.889

Gnomad EAS

AF:

0.842

Gnomad SAS

AF:

0.826

Gnomad FIN

AF:

0.879

Gnomad MID

AF:

0.823

Gnomad NFE

AF:

0.905

Gnomad OTH

AF:

0.799

GnomAD3 exomes

AF:

0.864

AC:

213610

AN:

247294

Hom.:

93698

AF XY:

0.868

AC XY:

116358

AN XY:

134096

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.933

Gnomad ASJ exome

AF:

0.881

Gnomad EAS exome

AF:

0.848

Gnomad SAS exome

AF:

0.831

Gnomad FIN exome

AF:

0.886

Gnomad NFE exome

AF:

0.903

Gnomad OTH exome

AF:

0.878

GnomAD4 exome

AF:

0.892

AC:

1300812

AN:

1459080

Hom.:

582883

Cov.:

AF XY:

0.891

AC XY:

646683

AN XY:

725786

show subpopulations

Gnomad4 AFR exome

AF:

0.481

Gnomad4 AMR exome

AF:

0.927

Gnomad4 ASJ exome

AF:

0.884

Gnomad4 EAS exome

AF:

0.850

Gnomad4 SAS exome

AF:

0.832

Gnomad4 FIN exome

AF:

0.891

Gnomad4 NFE exome

AF:

0.910

Gnomad4 OTH exome

AF:

0.863

GnomAD4 genome

AF:

0.781

AC:

118299

AN:

151398

Hom.:

48710

Cov.:

AF XY:

0.784

AC XY:

57965

AN XY:

73930

show subpopulations

Gnomad4 AFR

AF:

0.490

Gnomad4 AMR

AF:

0.883

Gnomad4 ASJ

AF:

0.889

Gnomad4 EAS

AF:

0.842

Gnomad4 SAS

AF:

0.826

Gnomad4 FIN

AF:

0.879

Gnomad4 NFE

AF:

0.905

Gnomad4 OTH

AF:

0.798

Alfa

AF:

0.879

Hom.:

122451

Bravo

AF:

0.769

TwinsUK

AF:

0.912

AC:

3381

ALSPAC

AF:

0.919

AC:

3543

ESP6500AA

AF:

0.497

AC:

2189

ESP6500EA

AF:

0.910

AC:

7829

ExAC

AF:

0.852

AC:

103350

Asia WGS

AF:

0.808

AC:

2808

AN:

3478

EpiCase

AF:

0.902

EpiControl

AF:

0.904

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala558Thr in exon 12 of DNAI2: This variant is not expected to have clinical sig nificance because it has been identified in 49.7% (2189/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1979370). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Primary ciliary dyskinesia 9

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Primary ciliary dyskinesia

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.0040

DANN

Benign

0.84

DEOGEN2

Benign

0.011

.;T;T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.27

T;.;T;T

MetaRNN

Benign

6.4e-7

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

.;N;N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.3

.;N;N;.

REVEL

Benign

0.076

Sift

Benign

0.45

.;T;T;.

Sift4G

Benign

0.60

T;T;T;T

Polyphen

0.0020

.;B;B;.

Vest4

0.050

MPC

0.23

ClinPred

0.027

GERP RS

-9.4

Varity_R

0.027

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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