chr7-72278781-G-A

Position:

• chr7-72278781-G-A

Variant summary

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

The NM_031468.4(CALN1):​c.149C>T​(p.Ala50Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,456 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CALN1 NM_031468.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.23

Genes affected

CALN1 (HGNC:13248): (calneuron 1) This gene encodes a protein with high similarity to the calcium-binding proteins of the calmodulin family. The encoded protein contains two EF-hand domains and potential calcium-binding sites. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

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	UniProt
CALN1	NM_031468.4	c.149C>T	p.Ala50Val	missense_variant	3/7	ENST00000395275.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALN1	ENST00000395275.7	c.149C>T	p.Ala50Val	missense_variant	3/7	5	NM_031468.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461456 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 05, 2023

The c.149C>T (p.A50V) alteration is located in exon 3 (coding exon 2) of the CALN1 gene. This alteration results from a C to T substitution at nucleotide position 149, causing the alanine (A) at amino acid position 50 to be replaced by a valine (V). 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	0.64
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.028	T;.;T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;D;.;D;D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.55	N;.;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.047	D;D;D;D;T
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.95	P;.;P;P;.
Vest4		0.81
MutPred		0.34		Gain of helix (P = 0.0117);.;Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);
MVP		0.69
MPC		1.8
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.18
gMVP		0.85

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: rs764214080; hg19: chr7-71743766;