1-8949409-G-A

Position:

• chr1-8949409-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001215.4(CA6):​c.226G>A​(p.Gly76Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CA6 NM_001215.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA6	NM_001215.4	c.226G>A	p.Gly76Arg	missense_variant	2/8	ENST00000377443.7	NP_001206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CA6	ENST00000377443.7	c.226G>A	p.Gly76Arg	missense_variant	2/8	1	NM_001215.4	ENSP00000366662.2
CA6	ENST00000480186.7	c.226G>A	p.Gly76Arg	missense_variant	2/3	2		ENSP00000435280.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461044 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 726876

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Nov 09, 2024

The c.226G>A (p.G76R) alteration is located in exon 2 (coding exon 2) of the CA6 gene. This alteration results from a G to A substitution at nucleotide position 226, causing the glycine (G) at amino acid position 76 to be replaced by an arginine (R). 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	0.34
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.4	.;M;M
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.12	T;T;T
Sift4G	Uncertain	0.022	D;T;T
Polyphen		1.0	.;D;.
Vest4		0.47
MutPred		0.46		Loss of catalytic residue at A75 (P = 0.0621);Loss of catalytic residue at A75 (P = 0.0621);Loss of catalytic residue at A75 (P = 0.0621);
MVP		0.76
MPC		0.70
ClinPred		0.90	D
GERP RS		4.4
Varity_R		0.39
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr1-9009468; COSMIC: COSV66263150;