2-10419953-G-A

Variant names:

• chr2-10419953-G-A
• rs1256159520
• NM_002149.4:c.196G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002149.4(HPCAL1):​c.196G>A​(p.Glu66Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HPCAL1 NM_002149.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.93

Genes affected

HPCAL1 (HGNC:5145): (hippocalcin like 1) The protein encoded by this gene is a member of neuron-specific calcium-binding proteins family found in the retina and brain. It is highly similar to human hippocalcin protein and nearly identical to the rat and mouse hippocalcin like-1 proteins. It may be involved in the calcium-dependent regulation of rhodopsin phosphorylation and may be of relevance for neuronal signalling in the central nervous system. Several alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPCAL1	NM_002149.4	c.196G>A	p.Glu66Lys	missense_variant	Exon 3 of 5	ENST00000307845.8	NP_002140.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPCAL1	ENST00000307845.8	c.196G>A	p.Glu66Lys	missense_variant	Exon 3 of 5	1	NM_002149.4	ENSP00000310749.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251102 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461668 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000413 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.196G>A (p.E66K) alteration is located in exon 4 (coding exon 1) of the HPCAL1 gene. This alteration results from a G to A substitution at nucleotide position 196, causing the glutamic acid (E) at amino acid position 66 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T;T;T;T;T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;.;D;.
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;L;L
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.7	D;D;.;.;.
REVEL	Uncertain	0.43
Sift	Benign	0.15	T;T;.;.;.
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.99	D;D;D;D;D
Vest4		0.91
MVP		0.47
MPC		1.5
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.52
gMVP		0.94

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: rs1256159520; hg19: chr2-10560079; COSMIC: COSV57145596; COSMIC: COSV57145596;