Genetic Variant NM_001315532.2:c.53C>T (chr22-36816953-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001315532.2(PVALB):c.53C>T(p.Ala18Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,420 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A18D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PVALB
NM_001315532.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.96

Publications

0 publications found

Variant links:

Genes affected

PVALB (HGNC:9704): (parvalbumin) The protein encoded by this gene is a high affinity calcium ion-binding protein that is structurally and functionally similar to calmodulin and troponin C. The encoded protein is thought to be involved in muscle relaxation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

PVALB links:

ENSG00000234979 (HGNC:):

ENSG00000234979 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001315532.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PVALB	NM_001315532.2	MANE Select	c.53C>T	p.Ala18Val	missense	Exon 1 of 4	NP_001302461.1	P20472
	PVALB	NM_002854.3		c.53C>T	p.Ala18Val	missense	Exon 2 of 5	NP_002845.1	P20472

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PVALB	ENST00000417718.7	TSL:1 MANE Select	c.53C>T	p.Ala18Val	missense	Exon 1 of 4	ENSP00000400247.2	P20472
PVALB	ENST00000216200.9	TSL:1	c.53C>T	p.Ala18Val	missense	Exon 2 of 5	ENSP00000216200.5	P20472
PVALB	ENST00000912200.1		c.53C>T	p.Ala18Val	missense	Exon 2 of 5	ENSP00000582259.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455420

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724020

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32898

American (AMR)

AF:

0.00

AC:

AN:

44414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26010

East Asian (EAS)

AF:

0.00

AC:

AN:

39374

South Asian (SAS)

AF:

0.00

AC:

AN:

85378

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4644

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110500

Other (OTH)

AF:

0.00

AC:

AN:

60106

⚠️ 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.93

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.52

MetaSVM

Uncertain

0.25

MutationAssessor

Pathogenic

3.4

PhyloP100

7.0

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.50

Sift

Uncertain

0.020

Sift4G

Benign

0.073

Polyphen

0.98

Vest4

0.51

MutPred

0.36

Loss of disorder (P = 0.0677)

MVP

0.55

MPC

0.35

ClinPred

0.99

GERP RS

4.0

PromoterAI

-0.076

Neutral

(source)

Varity_R

0.58

gMVP

0.82

Mutation Taster

=53/47

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over