Genetic Variant NM_023036.6:c.1574C>T (chr17-74312082-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_023036.6(DNAI2):c.1574C>T(p.Ala525Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,613,162 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A525A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 3 hom. )

Consequence

DNAI2
NM_023036.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 1.62

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAI2 links:

LOC105371891 (HGNC:):

LOC105371891 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071490705).

BP6

Variant 17-74312082-C-T is Benign according to our data. Variant chr17-74312082-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241450.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000466 (71/152270) while in subpopulation EAS AF = 0.00986 (51/5170). AF 95% confidence interval is 0.00771. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAI2	NM_023036.6	MANE Select	c.1574C>T	p.Ala525Val	missense	Exon 12 of 14	NP_075462.3	Q9GZS0-1
DNAI2	NM_001353167.2		c.1574C>T	p.Ala525Val	missense	Exon 12 of 15	NP_001340096.1
DNAI2	NM_001172810.3		c.1538C>T	p.Ala513Val	missense	Exon 12 of 14	NP_001166281.1	Q9GZS0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAI2	ENST00000311014.11	TSL:1 MANE Select	c.1574C>T	p.Ala525Val	missense	Exon 12 of 14	ENSP00000308312.6	Q9GZS0-1
DNAI2	ENST00000579490.5	TSL:1	c.1745C>T	p.Ala582Val	missense	Exon 11 of 13	ENSP00000464197.1	J3QRG2
DNAI2	ENST00000446837.2	TSL:1	c.1574C>T	p.Ala525Val	missense	Exon 11 of 13	ENSP00000400252.2	Q9GZS0-1

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00984

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000755

AC:

189

AN:

250302

AF XY:

0.000767

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00821

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000387

AC:

566

AN:

1460892

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

293

AN XY:

726720

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33442

American (AMR)

AF:

0.0000894

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00955

AC:

379

AN:

39700

South Asian (SAS)

AF:

0.000777

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.0000563

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.00288

AC:

AN:

5214

European-Non Finnish (NFE)

AF:

0.0000657

AC:

AN:

1111862

Other (OTH)

AF:

0.000365

AC:

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000466

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41548

American (AMR)

AF:

0.000262

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00986

AC:

AN:

5170

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000306

Hom.:

Bravo

AF:

0.000729

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000807

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (3)

Primary ciliary dyskinesia 9 (2)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.61

M_CAP

Benign

0.010

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.97

PhyloP100

1.6

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.088

Sift

Benign

0.14

Sift4G

Benign

0.25

Polyphen

0.0070

Vest4

0.092

MVP

0.73

MPC

0.24

ClinPred

0.068

GERP RS

1.4

Varity_R

0.048

gMVP

0.59

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over