Genetic Variant NM_002149.4:c.377A>G (chr2-10420134-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002149.4(HPCAL1):c.377A>G(p.Gln126Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q126H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

HPCAL1
NM_002149.4 missense, splice_region

Scores

Splicing: ADA: 0.9977

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.33

Publications

0 publications found

Variant links:

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]

HPCAL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002149.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPCAL1	NM_002149.4	MANE Select	c.377A>G	p.Gln126Arg	missense splice_region	Exon 3 of 5	NP_002140.2
HPCAL1	NM_001258357.2		c.377A>G	p.Gln126Arg	missense splice_region	Exon 3 of 5	NP_001245286.1	P37235
HPCAL1	NM_001258358.2		c.377A>G	p.Gln126Arg	missense splice_region	Exon 3 of 5	NP_001245287.1	P37235

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPCAL1	ENST00000307845.8	TSL:1 MANE Select	c.377A>G	p.Gln126Arg	missense splice_region	Exon 3 of 5	ENSP00000310749.3	P37235
HPCAL1	ENST00000419810.6	TSL:1	n.377A>G		splice_region non_coding_transcript_exon	Exon 5 of 8	ENSP00000416359.2	E9PC71
HPCAL1	ENST00000904548.1		c.377A>G	p.Gln126Arg	missense splice_region	Exon 3 of 5	ENSP00000574607.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.23

Eigen

Benign

-0.17

Eigen_PC

Benign

0.044

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.20

PhyloP100

7.3

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.33

Sift

Benign

0.31

Sift4G

Benign

0.50

Polyphen

0.0

Vest4

0.74

MutPred

0.40

Gain of MoRF binding (P = 0.0095)

MVP

0.65

MPC

1.3

ClinPred

0.83

GERP RS

4.7

PromoterAI

-0.16

Neutral

(source)

Varity_R

0.33

gMVP

0.89

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.26

Position offset: 41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over