2-10423043-A-G

Position:

• chr2-10423043-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002149.4(HPCAL1):​c.439A>G​(p.Lys147Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HPCAL1 NM_002149.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPCAL1	NM_002149.4	c.439A>G	p.Lys147Glu	missense_variant	4/5	ENST00000307845.8	NP_002140.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPCAL1	ENST00000307845.8	c.439A>G	p.Lys147Glu	missense_variant	4/5	1	NM_002149.4	ENSP00000310749	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The c.439A>G (p.K147E) alteration is located in exon 5 (coding exon 2) of the HPCAL1 gene. This alteration results from a A to G substitution at nucleotide position 439, causing the lysine (K) at amino acid position 147 to be replaced by a glutamic acid (E). 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	0.72
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;T;T;T
Eigen	Benign	-0.033
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;.;.;D;.
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.49	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.51	N;N;N;N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.6	D;D;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.062	T;T;.;.;.
Sift4G	Benign	0.54	T;T;T;T;T
Polyphen		0.020	B;B;B;B;B
Vest4		0.68
MutPred		0.27		Loss of ubiquitination at K147 (P = 0.0087);Loss of ubiquitination at K147 (P = 0.0087);Loss of ubiquitination at K147 (P = 0.0087);Loss of ubiquitination at K147 (P = 0.0087);Loss of ubiquitination at K147 (P = 0.0087);
MVP		0.71
MPC		1.7
ClinPred		0.94	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-10563169;