rs137928260

Variant names:

• chr22-36815119-C-G
• rs137928260
• NM_001315532.2:c.178G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-36815119-C-G
• chr22-36815119-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001315532.2(PVALB):​c.178G>C​(p.Glu60Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. E60K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PVALB NM_001315532.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56
• Publications: 3 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity PRVA_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

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.178G>C	p.Glu60Gln	missense	Exon 2 of 4	NP_001302461.1	P20472
	PVALB	NM_002854.3		c.178G>C	p.Glu60Gln	missense	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.178G>C	p.Glu60Gln	missense	Exon 2 of 4	ENSP00000400247.2	P20472
	PVALB	ENST00000216200.9	TSL:1	c.178G>C	p.Glu60Gln	missense	Exon 3 of 5	ENSP00000216200.5	P20472
	PVALB	ENST00000912200.1		c.178G>C	p.Glu60Gln	missense	Exon 3 of 5	ENSP00000582259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251284 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.66		Loss of ubiquitination at K55 (P = 0.1055)
MVP		0.66
MPC		0.93
ClinPred		0.99	D
GERP RS		5.2
PromoterAI		-0.040	Neutral
Varity_R		0.75
gMVP		0.79
Mutation Taster		=35/65	disease causing

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: rs137928260; hg19: chr22-37211163; COSMIC: COSV53413338; COSMIC: COSV53413338;