1-8967814-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001215.4(CA6):c.727C>G(p.Gln243Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CA6 NM_001215.4 missense, splice_region
• Scores: Splicing: ADA: 0.8545
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02

Genes affected

CA6 (HGNC:1380): (carbonic anhydrase 6) The protein encoded by this gene is one of several isozymes of carbonic anhydrase. This protein is found only in salivary glands and saliva and protein may play a role in the reversible hydratation of carbon dioxide though its function in saliva is unknown. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA6	NM_001215.4	c.727C>G	p.Gln243Glu	missense_variant, splice_region_variant	6/8	ENST00000377443.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA6	ENST00000377443.7	c.727C>G	p.Gln243Glu	missense_variant, splice_region_variant	6/8	1	NM_001215.4	P2
CA6	ENST00000377436.6	c.727C>G	p.Gln243Glu	missense_variant, splice_region_variant	6/8	1		A2
CA6	ENST00000377442.3	c.547C>G	p.Gln183Glu	missense_variant, splice_region_variant	5/7	1
CA6	ENST00000476083.1	n.417C>G		splice_region_variant, non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Jan 06, 2023

The c.727C>G (p.Q243E) alteration is located in exon 6 (coding exon 6) of the CA6 gene. This alteration results from a C to G substitution at nucleotide position 727, causing the glutamine (Q) at amino acid position 243 to be replaced by a glutamic acid (E). 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	0.33
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.7	H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.77
MutPred		0.94		Loss of MoRF binding (P = 0.0444);Loss of MoRF binding (P = 0.0444);.;
MVP		0.90
MPC		0.67
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Benign	0.53
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: chr1-9027873;