rs199642068

Variant names:

• chr1-86432365-T-G
• rs199642068
• NM_006536.7:c.585-4T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_006536.7(CLCA2):​c.585-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,612,406 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: CLCA2 NM_006536.7 splice_region, intron
• Scores: Splicing: ADA: 0.008560
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0280
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 1-86432365-T-G is Benign according to our data. Variant chr1-86432365-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2638908.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 212 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.585-4T>G		splice_region intron	N/A	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.585-4T>G		splice_region intron	N/A	ENSP00000359596.4	Q9UQC9

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00141 AC: 352 AN: 249792 AF XY: 0.00126

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000383

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00146 AC: 2126 AN: 1460052 Hom.: 5 Cov.: 31 AF XY: 0.00142 AC XY: 1030 AN XY: 726410

African (AFR) AF: 0.000210 AC: 7 AN: 33256

American (AMR) AF: 0.000409 AC: 18 AN: 44012

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 377 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85918

European-Finnish (FIN) AF: 0.00155 AC: 83 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00137 AC: 1525 AN: 1111618

Other (OTH) AF: 0.00186 AC: 112 AN: 60308

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74498

African (AFR) AF: 0.000529 AC: 22 AN: 41586

American (AMR) AF: 0.000327 AC: 5 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00224 Hom.: 1

Bravo AF: 0.00124

EpiCase AF: 0.00207

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	8.6
DANN	Benign	0.94
PhyloP100		-0.028
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0086
dbscSNV1_RF	Benign	0.094
SpliceAI score (max)		0.010		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: rs199642068; hg19: chr1-86898048;