rs59629215

Variant names:

• chr17-74310152-G-A
• rs28725418
• NM_023036.6:c.1483G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_023036.6(DNAI2):​c.1483G>A​(p.Val495Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0761 in 1,613,358 control chromosomes in the GnomAD database, including 11,182 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V495V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.17 (4656 hom., cov: 32)
  • Exomes 𝑓: 0.066 (6526 hom.)
• Consequence: DNAI2 NM_023036.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.415
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC105371891 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.1497085E-5).
• BP6: Variant 17-74310152-G-A is Benign according to our data. Variant chr17-74310152-G-A is described in ClinVar as Benign. ClinVar VariationId is 226610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI2	NM_023036.6	c.1483G>A	p.Val495Ile	missense_variant	Exon 11 of 14	ENST00000311014.11	NP_075462.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAI2	ENST00000311014.11	c.1483G>A	p.Val495Ile	missense_variant	Exon 11 of 14	1	NM_023036.6	ENSP00000308312.6

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25953 AN: 151972 Hom.: 4628 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.0791

Gnomad AMR AF: 0.0842

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.0605

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0768

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0525

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.0905 AC: 22659 AN: 250424 AF XY: 0.0858

Gnomad AFR exome AF: 0.475

Gnomad AMR exome AF: 0.0456

Gnomad ASJ exome AF: 0.0617

Gnomad EAS exome AF: 0.0592

Gnomad FIN exome AF: 0.0730

Gnomad NFE exome AF: 0.0536

Gnomad OTH exome AF: 0.0746

GnomAD4 exome AF: 0.0662 AC: 96796 AN: 1461268 Hom.: 6526 Cov.: 36 AF XY: 0.0662 AC XY: 48147 AN XY: 726970

African (AFR) AF: 0.470 AC: 15730 AN: 33478

American (AMR) AF: 0.0509 AC: 2278 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 1569 AN: 26136

East Asian (EAS) AF: 0.0656 AC: 2603 AN: 39696

South Asian (SAS) AF: 0.116 AC: 9990 AN: 86258

European-Finnish (FIN) AF: 0.0689 AC: 3639 AN: 52844

Middle Eastern (MID) AF: 0.110 AC: 633 AN: 5766

European-Non Finnish (NFE) AF: 0.0494 AC: 54925 AN: 1111984

Other (OTH) AF: 0.0899 AC: 5429 AN: 60388

GnomAD4 genome AF: 0.171 AC: 26032 AN: 152090 Hom.: 4656 Cov.: 32 AF XY: 0.168 AC XY: 12518 AN XY: 74350

African (AFR) AF: 0.455 AC: 18850 AN: 41436

American (AMR) AF: 0.0840 AC: 1285 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 211 AN: 3470

East Asian (EAS) AF: 0.0607 AC: 313 AN: 5160

South Asian (SAS) AF: 0.116 AC: 558 AN: 4820

European-Finnish (FIN) AF: 0.0768 AC: 814 AN: 10596

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0525 AC: 3572 AN: 68004

Other (OTH) AF: 0.154 AC: 324 AN: 2110

Alfa AF: 0.0914 Hom.: 3780

Bravo AF: 0.183

TwinsUK AF: 0.0502 AC: 186

ALSPAC AF: 0.0459 AC: 177

ESP6500AA AF: 0.436 AC: 1920

ESP6500EA AF: 0.0484 AC: 416

ExAC AF: 0.0990 AC: 12018

Asia WGS AF: 0.124 AC: 434 AN: 3478

EpiCase AF: 0.0555

EpiControl AF: 0.0553

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val495Ile in exon 11 of DNAI2: This variant is not expected to have clinical s ignificance because it has been identified in 47% (4842/10248) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs28725418). -

Primary ciliary dyskinesia 9 Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2018

GeneDx

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	0.066
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.50
DANN	Benign	0.79
DEOGEN2	Benign	0.0056	.;T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.12	T;.;T;T
MetaRNN	Benign	0.000061	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.2	.;N;N;.
PhyloP100		0.41
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.42	.;N;N;.
REVEL	Benign	0.017
Sift	Benign	0.32	.;T;T;.
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.049
MPC		0.19
ClinPred		0.0015	T
GERP RS		-1.1
Varity_R		0.030
gMVP		0.29
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28725418; hg19: chr17-72306291;