chr17-74310152-G-A

Position:

• chr17-74310152-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 226610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-74310152-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
DNAI2	NM_023036.6	c.1483G>A	p.Val495Ile	missense_variant	11/14	ENST00000311014.11	NP_075462.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI2	ENST00000311014.11	c.1483G>A	p.Val495Ile	missense_variant	11/14	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

GnomAD3 exomes AF: 0.0905 AC: 22659 AN: 250424 Hom.: 2401 AF XY: 0.0858 AC XY: 11638 AN XY: 135606

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 SAS exome AF: 0.118

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

Gnomad4 AFR exome AF: 0.470

Gnomad4 AMR exome AF: 0.0509

Gnomad4 ASJ exome AF: 0.0600

Gnomad4 EAS exome AF: 0.0656

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.0689

Gnomad4 NFE exome AF: 0.0494

Gnomad4 OTH exome AF: 0.0899

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

Gnomad4 AFR AF: 0.455

Gnomad4 AMR AF: 0.0840

Gnomad4 ASJ AF: 0.0608

Gnomad4 EAS AF: 0.0607

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.0768

Gnomad4 NFE AF: 0.0525

Gnomad4 OTH AF: 0.154

Alfa AF: 0.0729 Hom.: 1609

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

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 11, 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	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2015	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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, 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 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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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;.
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

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

Other links and lift over

dbSNP: rs28725418; hg19: chr17-72306291;