dbSNP rs151241589: DNAI2:p.Pro572Leu (chr17-74312223-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.1715C>T(p.Pro572Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,578,290 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. P572P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0013 ( 9 hom. )

Consequence

DNAI2
NM_023036.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.535

Publications

4 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:

ENSG00000309634 (HGNC:):

ENSG00000309634 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=0.007289797).

BP6

Variant 17-74312223-C-T is Benign according to our data. Variant chr17-74312223-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261644.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00105 (150/143340) while in subpopulation SAS AF = 0.00832 (36/4326). AF 95% confidence interval is 0.00618. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 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.1715C>T	p.Pro572Leu	missense	Exon 12 of 14	NP_075462.3	Q9GZS0-1
DNAI2	NM_001353167.2		c.1715C>T	p.Pro572Leu	missense	Exon 12 of 15	NP_001340096.1
DNAI2	NM_001172810.3		c.1679C>T	p.Pro560Leu	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.1715C>T	p.Pro572Leu	missense	Exon 12 of 14	ENSP00000308312.6	Q9GZS0-1
DNAI2	ENST00000579490.5	TSL:1	c.1886C>T	p.Pro629Leu	missense	Exon 11 of 13	ENSP00000464197.1	J3QRG2
DNAI2	ENST00000446837.2	TSL:1	c.1715C>T	p.Pro572Leu	missense	Exon 11 of 13	ENSP00000400252.2	Q9GZS0-1

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

151

AN:

143212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000308

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000142

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000665

Gnomad SAS

AF:

0.00856

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00150

GnomAD2 exomes

AF:

0.00154

AC:

325

AN:

210886

AF XY:

0.00191

show subpopulations

Gnomad AFR exome

AF:

0.000157

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000636

Gnomad FIN exome

AF:

0.00230

Gnomad NFE exome

AF:

0.000911

Gnomad OTH exome

AF:

0.000746

GnomAD4 exome

AF:

0.00134

AC:

1917

AN:

1434950

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

1090

AN XY:

712290

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

31600

American (AMR)

AF:

0.000144

AC:

AN:

41760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25556

East Asian (EAS)

AF:

0.0000262

AC:

AN:

38108

South Asian (SAS)

AF:

0.00673

AC:

561

AN:

83322

European-Finnish (FIN)

AF:

0.00265

AC:

135

AN:

50894

Middle Eastern (MID)

AF:

0.00185

AC:

AN:

5404

European-Non Finnish (NFE)

AF:

0.00103

AC:

1137

AN:

1099242

Other (OTH)

AF:

0.00103

AC:

AN:

59064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

181

271

362

452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.00105

AC:

150

AN:

143340

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

69346

show subpopulations

African (AFR)

AF:

0.000307

AC:

AN:

39040

American (AMR)

AF:

0.000142

AC:

AN:

14092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3374

East Asian (EAS)

AF:

0.000665

AC:

AN:

4510

South Asian (SAS)

AF:

0.00832

AC:

AN:

4326

European-Finnish (FIN)

AF:

0.00255

AC:

AN:

8620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

66200

Other (OTH)

AF:

0.00149

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.00102

Hom.:

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Primary ciliary dyskinesia (2)

Primary ciliary dyskinesia 9 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.012

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

0.54

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.70

REVEL

Benign

0.064

Sift

Benign

0.076

Sift4G

Benign

0.28

Polyphen

0.0050

Vest4

0.22

MVP

0.47

MPC

0.26

ClinPred

0.0033

GERP RS

-1.6

Varity_R

0.032

gMVP

0.19

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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