22-36815104-C-T

Position:

• chr22-36815104-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001315532.2(PVALB):​c.193G>A​(p.Gly65Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,614,156 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (38 hom.)
• Consequence: PVALB NM_001315532.2 missense, splice_region
• Scores: Splicing: ADA: 0.04565
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.22

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035583377).
• BP6: Variant 22-36815104-C-T is Benign according to our data. Variant chr22-36815104-C-T is described in ClinVar as [Benign]. Clinvar id is 781615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1640/152310) while in subpopulation AFR AF= 0.0383 (1591/41564). AF 95% confidence interval is 0.0367. There are 26 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 GnomAd4 at 26 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PVALB	NM_001315532.2	c.193G>A	p.Gly65Arg	missense_variant, splice_region_variant	2/4	ENST00000417718.7	NP_001302461.1
PVALB	NM_002854.3	c.193G>A	p.Gly65Arg	missense_variant, splice_region_variant	3/5		NP_002845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PVALB	ENST00000417718.7	c.193G>A	p.Gly65Arg	missense_variant, splice_region_variant	2/4	1	NM_001315532.2	ENSP00000400247	P1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1636 AN: 152192 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

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: 0.0000588

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00270 AC: 678 AN: 251140 Hom.: 11 AF XY: 0.00194 AC XY: 263 AN XY: 135766

Gnomad AFR exome AF: 0.0380

Gnomad AMR exome AF: 0.00153

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: 0.00109 AC: 1596 AN: 1461846 Hom.: 38 Cov.: 31 AF XY: 0.000935 AC XY: 680 AN XY: 727218

Gnomad4 AFR exome AF: 0.0405

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.0108 AC: 1640 AN: 152310 Hom.: 26 Cov.: 32 AF XY: 0.0102 AC XY: 761 AN XY: 74464

Gnomad4 AFR AF: 0.0383

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00175 Hom.: 8

Bravo AF: 0.0125

ESP6500AA AF: 0.0379 AC: 167

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00343 AC: 416

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.62	D
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.33	N;N;.;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	2.6	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.073	T;T;D;D
Sift4G	Benign	0.33	T;T;T;.
Polyphen		0.025	B;B;.;.
Vest4		0.42
MutPred		0.46		Loss of ubiquitination at K69 (P = 0.0834);Loss of ubiquitination at K69 (P = 0.0834);.;Loss of ubiquitination at K69 (P = 0.0834);
MVP		0.24
MPC		0.34
ClinPred		0.020	T
GERP RS		3.0
Varity_R		0.22
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.046
dbscSNV1_RF	Benign	0.31
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: rs147596087; hg19: chr22-37211148; COSMIC: COSV99064741; COSMIC: COSV99064741;