22-36815175-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001315532.2(PVALB):c.122C>T(p.Ala41Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,614,110 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (38 hom.)
• Consequence: PVALB NM_001315532.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.34

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021724403).
• BP6: Variant 22-36815175-G-A is Benign according to our data. Variant chr22-36815175-G-A is described in ClinVar as [Benign]. Clinvar id is 781616.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1646/152250) while in subpopulation AFR AF= 0.0383 (1592/41530). AF 95% confidence interval is 0.0368. There are 27 homozygotes in gnomad4. There are 761 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PVALB	NM_001315532.2	c.122C>T	p.Ala41Val	missense_variant	2/4	ENST00000417718.7
PVALB	NM_002854.3	c.122C>T	p.Ala41Val	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PVALB	ENST00000417718.7	c.122C>T	p.Ala41Val	missense_variant	2/4	1	NM_001315532.2	P1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1642 AN: 152132 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00272 AC: 683 AN: 251448 Hom.: 11 AF XY: 0.00196 AC XY: 266 AN XY: 135904

Gnomad AFR exome AF: 0.0381

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00110 AC: 1611 AN: 1461860 Hom.: 38 Cov.: 31 AF XY: 0.000946 AC XY: 688 AN XY: 727232

Gnomad4 AFR exome AF: 0.0406

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.0108 AC: 1646 AN: 152250 Hom.: 27 Cov.: 32 AF XY: 0.0102 AC XY: 761 AN XY: 74436

Gnomad4 AFR AF: 0.0383

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00182 Hom.: 9

Bravo AF: 0.0126

ESP6500AA AF: 0.0377 AC: 166

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00345 AC: 419

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.29	T;T;T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.043	D;D;T;D
Sift4G	Benign	0.30	T;T;T;.
Polyphen		0.0	B;B;.;.
Vest4		0.26
MVP		0.35
MPC		0.26
ClinPred		0.013	T
GERP RS		1.7
Varity_R		0.068
gMVP		0.46

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

Other links and lift over

dbSNP: rs74804322; hg19: chr22-37211219; COSMIC: COSV99064742; COSMIC: COSV99064742;