NM_001315532.2:c.193G>A

Variant names:

• chr22-36815104-C-T
• rs147596087
• NM_001315532.2:c.193G>A

Variant summary

Our verdict is Benign. The variant received -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. 16/23 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
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 gene

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.193G>A	p.Gly65Arg	missense splice_region	Exon 2 of 4	NP_001302461.1	P20472
	PVALB	NM_002854.3		c.193G>A	p.Gly65Arg	missense splice_region	Exon 3 of 5	NP_002845.1	P20472

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PVALB	ENST00000417718.7	TSL:1 MANE Select	c.193G>A	p.Gly65Arg	missense splice_region	Exon 2 of 4	ENSP00000400247.2	P20472
	PVALB	ENST00000216200.9	TSL:1	c.193G>A	p.Gly65Arg	missense splice_region	Exon 3 of 5	ENSP00000216200.5	P20472
	PVALB	ENST00000912200.1		c.193G>A	p.Gly65Arg	missense splice_region	Exon 3 of 5	ENSP00000582259.1

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

GnomAD2 exomes AF: 0.00270 AC: 678 AN: 251140 AF XY: 0.00194

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 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

African (AFR) AF: 0.0405 AC: 1355 AN: 33478

American (AMR) AF: 0.00199 AC: 89 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111988

Other (OTH) AF: 0.00202 AC: 122 AN: 60390

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

African (AFR) AF: 0.0383 AC: 1591 AN: 41564

American (AMR) AF: 0.00209 AC: 32 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00419 Hom.: 23

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.62	D
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.33	N
PhyloP100		3.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.12
Sift	Benign	0.073	T
Sift4G	Benign	0.33	T
Polyphen		0.025	B
Vest4		0.42
MutPred		0.46		Loss of ubiquitination at K69 (P = 0.0834)
MVP		0.24
MPC		0.34
ClinPred		0.020	T
GERP RS		3.0
PromoterAI		0.11	Neutral
Varity_R		0.22
gMVP		0.71
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs147596087; hg19: chr22-37211148; COSMIC: COSV99064741; COSMIC: COSV99064741;