rs879253800

Positions:

• chr15-63338833-G-GAGGT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001218.5(CA12):​c.859_860insACCT​(p.Thr287AsnfsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CA12 NM_001218.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.28

Genes affected

CA12 (HGNC:1371): (carbonic anhydrase 12) Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. This gene product is a type I membrane protein that is highly expressed in normal tissues, such as kidney, colon and pancreas, and has been found to be overexpressed in 10% of clear cell renal carcinomas. Three transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2014]

LOC124903506 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-63338833-G-GAGGT is Pathogenic according to our data. Variant chr15-63338833-G-GAGGT is described in ClinVar as [Pathogenic]. Clinvar id is 218367.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA12	NM_001218.5	c.859_860insACCT	p.Thr287AsnfsTer51	frameshift_variant	8/11	ENST00000178638.8	NP_001209.1
LOC124903506	XR_007064676.1	n.768-2981_768-2980insAGGT		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CA12	ENST00000178638.8	c.859_860insACCT	p.Thr287AsnfsTer51	frameshift_variant	8/11	1	NM_001218.5	ENSP00000178638	A1
CA12	ENST00000344366.7	c.859_860insACCT	p.Thr287AsnfsTer40	frameshift_variant	8/10	1		ENSP00000343088	P4
CA12	ENST00000422263.2	c.679_680insACCT	p.Thr227AsnfsTer40	frameshift_variant	7/9	2		ENSP00000403028

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Isolated hyperchlorhidrosis Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 27, 2018	- -
Pathogenic, criteria provided, single submitter	research	Garry R Cutting Laboratory, Johns Hopkins University	Oct 20, 2015	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs879253800; hg19: chr15-63631032;