chr1-86468986-G-C

Position:

• chr1-86468986-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001285.4(CLCA1):​c.15G>C​(p.Lys5Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCA1 NM_001285.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

Genes affected

CLCA1 (HGNC:2015): (chloride channel accessory 1) This gene encodes a member of the calcium sensitive chloride conductance protein family. To date, all members of this gene family map to the same region on chromosome 1p31-p22 and share a high degree of homology in size, sequence, and predicted structure, but differ significantly in their tissue distributions. The encoded protein is expressed as a precursor protein that is processed into two cell-surface-associated subunits, although the site at which the precursor is cleaved has not been precisely determined. The encoded protein may be involved in mediating calcium-activated chloride conductance in the intestine. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41331303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCA1	NM_001285.4	c.15G>C	p.Lys5Asn	missense_variant	1/14	ENST00000394711.2	NP_001276.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCA1	ENST00000394711.2	c.15G>C	p.Lys5Asn	missense_variant	1/14	1	NM_001285.4	ENSP00000378200.1
CLCA1	ENST00000234701.7	c.15G>C	p.Lys5Asn	missense_variant	2/15	1		ENSP00000234701.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 247198 Hom.: 0 AF XY: 0.00000749 AC XY: 1 AN XY: 133518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

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 Cov.: 30

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

Jan 24, 2024

The c.15G>C (p.K5N) alteration is located in exon 1 (coding exon 1) of the CLCA1 gene. This alteration results from a G to C substitution at nucleotide position 15, causing the lysine (K) at amino acid position 5 to be replaced by an asparagine (N). 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	Benign	0.25
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T;T
Eigen	Benign	0.026
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.71	.;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.13
Sift	Benign	0.081	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.99	D;D
Vest4		0.41
MutPred		0.53		Loss of methylation at S5 (P = 0.0058);Loss of methylation at S5 (P = 0.0058);
MVP		0.46
MPC		0.41
ClinPred		0.47	T
GERP RS		3.1
Varity_R		0.065
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs375828178; hg19: chr1-86934669;