rs117932646

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_023036.6(DNAI2):c.1660G>A(p.Asp554Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,533,352 control chromosomes in the GnomAD database, including 23 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D554H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 19 hom. )

Consequence

DNAI2
NM_023036.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.391

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:

LOC105371891 (HGNC:):

LOC105371891 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=0.0027095377).

BP6

Variant 17-74312168-G-A is Benign according to our data. Variant chr17-74312168-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 325023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00178 (265/149002) while in subpopulation EAS AF= 0.0229 (111/4850). AF 95% confidence interval is 0.0194. There are 4 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI2	NM_023036.6 linkuse as main transcript	c.1660G>A	p.Asp554Asn	missense_variant	12/14	ENST00000311014.11
LOC105371891	XR_934971.3 linkuse as main transcript	n.294C>T		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI2	ENST00000311014.11 linkuse as main transcript	c.1660G>A	p.Asp554Asn	missense_variant	12/14	1	NM_023036.6	P2	Q9GZS0-1

Frequencies

GnomAD3 genomes

AF:

0.00178

AC:

265

AN:

148876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0228

Gnomad SAS

AF:

0.000654

Gnomad FIN

AF:

0.0116

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000417

Gnomad OTH

AF:

0.00194

GnomAD3 exomes

AF:

0.00353

AC:

877

AN:

248576

Hom.:

AF XY:

0.00325

AC XY:

438

AN XY:

134730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0253

Gnomad SAS exome

AF:

0.000295

Gnomad FIN exome

AF:

0.0132

Gnomad NFE exome

AF:

0.000958

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00153

AC:

2113

AN:

1384350

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

1007

AN XY:

687742

show subpopulations

Gnomad4 AFR exome

AF:

0.0000644

Gnomad4 AMR exome

AF:

0.000118

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0280

Gnomad4 SAS exome

AF:

0.000246

Gnomad4 FIN exome

AF:

0.0140

Gnomad4 NFE exome

AF:

0.000366

Gnomad4 OTH exome

AF:

0.00221

GnomAD4 genome

AF:

0.00178

AC:

265

AN:

149002

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

160

AN XY:

72620

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000268

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0229

Gnomad4 SAS

AF:

0.000654

Gnomad4 FIN

AF:

0.0116

Gnomad4 NFE

AF:

0.000417

Gnomad4 OTH

AF:

0.00192

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.00102

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00348

AC:

422

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000297

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 30, 2022	This alteration is classified as likely 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	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Primary ciliary dyskinesia 9

Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

2.3

DANN

Benign

0.83

DEOGEN2

Benign

0.0041

.;T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.75

T;.;T;T

MetaRNN

Benign

0.0027

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L;L;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.1

.;N;N;.

REVEL

Benign

0.038

Sift

Benign

0.47

.;T;T;.

Sift4G

Benign

0.60

T;T;T;T

Polyphen

0.0040

.;B;B;.

Vest4

0.10

MVP

0.59

MPC

0.23

ClinPred

0.024

GERP RS

-1.1

Varity_R

0.032

gMVP

0.44

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