chr1-86425384-A-T

Variant names:

• chr1-86425384-A-T
• rs756044978
• NM_006536.7:c.232A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006536.7(CLCA2):​c.232A>T​(p.Arg78*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,428,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: CLCA2 NM_006536.7 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 0 publications found

Genes affected

CLCA2 (HGNC:2016): (chloride channel accessory 2) This gene encodes a member of the calcium-activated chloride channel regulator (CLCR) family of proteins. Members of this family regulate the transport of chloride across the plasma membrane. The encoded protein is autoproteolytically processed to generate N- and C- terminal fragments. Expression of this gene is upregulated by the tumor suppressor protein p53 in response to DNA damage. In breast cancer, expression of this gene is downregulated and the encoded protein may inhibit migration and invasion while promoting mesenchymal-to-epithelial transition in cancer cell lines. [provided by RefSeq, Sep 2016]

CLCA2 Gene-Disease associations (from GenCC):

• heart conduction disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006536.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCA2	NM_006536.7	MANE Select	c.232A>T	p.Arg78*	stop_gained	Exon 2 of 14	NP_006527.1	Q9UQC9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCA2	ENST00000370565.5	TSL:1 MANE Select	c.232A>T	p.Arg78*	stop_gained	Exon 2 of 14	ENSP00000359596.4	Q9UQC9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 237228 AF XY: 0.00000780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000909

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000560 AC: 8 AN: 1428274 Hom.: 0 Cov.: 28 AF XY: 0.00000847 AC XY: 6 AN XY: 708500

African (AFR) AF: 0.00 AC: 0 AN: 32378

American (AMR) AF: 0.00 AC: 0 AN: 41110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25136

East Asian (EAS) AF: 0.00 AC: 0 AN: 38928

South Asian (SAS) AF: 0.00 AC: 0 AN: 79336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.00000640 AC: 7 AN: 1094456

Other (OTH) AF: 0.0000170 AC: 1 AN: 58916

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Benign	0.64	D
PhyloP100		1.1
Vest4		0.77
GERP RS		4.8
Mutation Taster		=66/134	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs756044978; hg19: chr1-86891067;