Genetic Variant CA12:p.Thr346Ser (chr15-63326313-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001218.5(CA12):c.1037C>G(p.Thr346Ser) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T346N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CA12
NM_001218.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.899

Publications

0 publications found

Variant links:

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]

CA12 Gene-Disease associations (from GenCC):

isolated hyperchlorhidrosis
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

CA12 links:

LOC124903506 (HGNC:):

LOC124903506 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.053625762).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001218.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CA12	NM_001218.5	MANE Select	c.1037C>G	p.Thr346Ser	missense	Exon 11 of 11	NP_001209.1	O43570-1
CA12	NM_206925.3		c.1004C>G	p.Thr335Ser	missense	Exon 10 of 10	NP_996808.1	O43570-2
CA12	NM_001293642.2		c.824C>G	p.Thr275Ser	missense	Exon 9 of 9	NP_001280571.1	B3KUB4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CA12	ENST00000178638.8	TSL:1 MANE Select	c.1037C>G	p.Thr346Ser	missense	Exon 11 of 11	ENSP00000178638.3	O43570-1
CA12	ENST00000344366.7	TSL:1	c.1004C>G	p.Thr335Ser	missense	Exon 10 of 10	ENSP00000343088.3	O43570-2
CA12	ENST00000907869.1		c.1031C>G	p.Thr344Ser	missense	Exon 11 of 11	ENSP00000577928.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

3.1

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.10

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.66

M_CAP

Benign

0.017

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.90

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.37

REVEL

Benign

0.084

Sift

Benign

0.077

Sift4G

Benign

0.24

Polyphen

0.094

Vest4

0.048

MutPred

0.16

Gain of disorder (P = 0.0519)

MVP

0.62

MPC

0.14

ClinPred

0.064

GERP RS

2.2

Varity_R

0.043

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over