1-86574591-G-C

Position:

• chr1-86574591-G-C

Variant summary

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

The NM_012128.4(CLCA4):​c.1519G>C​(p.Val507Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCA4 NM_012128.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75

Genes affected

CLCA4 (HGNC:2018): (chloride channel accessory 4) The protein encoded by this gene belongs to the calcium sensitive chloride conductance protein family. To date, all members of this gene family map to the same site on chromosome 1p31-p22 and share high degrees of homology in size, sequence and predicted structure, but differ significantly in their tissue distributions. Alternative splicing results in multiple transcript variants, only one of which is thought to be protein coding. [provided by RefSeq, Dec 2008]

CLCA4 (HGNC:):

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
CLCA4	NM_012128.4	c.1519G>C	p.Val507Leu	missense_variant	10/14	ENST00000370563.3	NP_036260.2
CLCA4	XM_011541015.3	c.1366G>C	p.Val456Leu	missense_variant	10/14		XP_011539317.1
CLCA4	NR_024602.2	n.1452G>C		non_coding_transcript_exon_variant	9/13
CLCA4-AS1	NR_135837.1	n.1293-3183C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCA4	ENST00000370563.3	c.1519G>C	p.Val507Leu	missense_variant	10/14	1	NM_012128.4	ENSP00000359594.3
CLCA4-AS1	ENST00000456587.1	n.295-3183C>G		intron_variant		3
CLCA4-AS1	ENST00000650379.1	n.2258-3183C>G		intron_variant
CLCA4-AS1	ENST00000699483.1	n.1284-3183C>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Mar 20, 2024

The c.1519G>C (p.V507L) alteration is located in exon 10 (coding exon 10) of the CLCA4 gene. This alteration results from a G to C substitution at nucleotide position 1519, causing the valine (V) at amino acid position 507 to be replaced by a leucine (L). 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	0.28
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0091	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.24
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.73		Gain of loop (P = 0.2045);
MVP		0.60
MPC		0.21
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.22
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr1-87040274; COSMIC: COSV55367081; COSMIC: COSV55367081;