Genetic Variant NPIPA2:p.Cys311Cys (chr16-14765236-T-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7

The NM_001395485.2(NPIPA2):c.933T>C(p.Cys311Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 18)

Exomes 𝑓: 0.00029 ( 8 hom. )

Failed GnomAD Quality Control

Consequence

NPIPA2
NM_001395485.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.22

Publications

1 publications found

Variant links:

Genes affected

NPIPA2 (HGNC:41979): (nuclear pore complex interacting protein family member A2) Predicted to be involved in mRNA transport and protein transport. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NPIPA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.04).

BP7

Synonymous conserved (PhyloP=-2.22 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPIPA2	NM_001395485.2 link	c.933T>C	p.Cys311Cys	synonymous_variant	Exon 10 of 10	ENST00000529166.6	NP_001382414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPIPA2	ENST00000529166.6 link	c.933T>C	p.Cys311Cys	synonymous_variant	Exon 10 of 10	5	NM_001395485.2	ENSP00000432029.1		E9PIF3
NPIPA2	ENST00000553201.1 link	c.876T>C	p.Cys292Cys	synonymous_variant	Exon 8 of 8	1		ENSP00000446882.1		A0A0B4J2F6

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

249

AN:

123100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00643

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00107

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000185

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000827

AC:

AN:

60458

AF XY:

0.000609

show subpopulations

Gnomad AFR exome

AF:

0.00783

Gnomad AMR exome

AF:

0.000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000504

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000288

AC:

398

AN:

1381774

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

168

AN XY:

690808

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00856

AC:

279

AN:

32594

American (AMR)

AF:

0.000877

AC:

AN:

44484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25546

East Asian (EAS)

AF:

0.00

AC:

AN:

39328

South Asian (SAS)

AF:

0.0000704

AC:

AN:

85266

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39344

Middle Eastern (MID)

AF:

0.000249

AC:

AN:

4016

European-Non Finnish (NFE)

AF:

0.0000123

AC:

AN:

1053014

Other (OTH)

AF:

0.00103

AC:

AN:

58182

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.318

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00204

AC:

251

AN:

123188

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

120

AN XY:

59394

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00647

AC:

237

AN:

36628

American (AMR)

AF:

0.00107

AC:

AN:

12170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2826

East Asian (EAS)

AF:

0.00

AC:

AN:

4396

South Asian (SAS)

AF:

0.00

AC:

AN:

3476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.0000185

AC:

AN:

54150

Other (OTH)

AF:

0.00

AC:

AN:

1650

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.341

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:

0.00341

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

2.4

(source)

DANN

Benign

0.32

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over