22-36816953-G-C

Variant names:

• chr22-36816953-G-C
• rs773030993
• NM_001315532.2:c.53C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001315532.2(PVALB):​c.53C>G​(p.Ala18Gly) 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. In-silico tool predicts a benign outcome for this variant. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.96
• Publications: 0 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]

ENSG00000234979 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3667065).

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>G	p.Ala18Gly	missense	Exon 1 of 4	NP_001302461.1	P20472
	PVALB	NM_002854.3		c.53C>G	p.Ala18Gly	missense	Exon 2 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.53C>G	p.Ala18Gly	missense	Exon 1 of 4	ENSP00000400247.2	P20472
	PVALB	ENST00000216200.9	TSL:1	c.53C>G	p.Ala18Gly	missense	Exon 2 of 5	ENSP00000216200.5	P20472
	PVALB	ENST00000912200.1		c.53C>G	p.Ala18Gly	missense	Exon 2 of 5	ENSP00000582259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455420 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724020

African (AFR) AF: 0.00 AC: 0 AN: 32898

American (AMR) AF: 0.00 AC: 0 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.00 AC: 0 AN: 85378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4644

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110500

Other (OTH) AF: 0.00 AC: 0 AN: 60106

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.35
Sift	Benign	0.20	T
Sift4G	Benign	0.26	T
Polyphen		0.63	P
Vest4		0.43
MutPred		0.27		Gain of ubiquitination at K14 (P = 0.0945)
MVP		0.54
MPC		0.28
ClinPred		0.96	D
GERP RS		4.0
PromoterAI		-0.027	Neutral
Varity_R		0.47
gMVP		0.74
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs773030993; hg19: chr22-37212997;