chr1-8949409-G-A

Variant names:

• chr1-8949409-G-A
• NM_001215.4:c.226G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Synonymous variant affecting the same amino acid position (i.e. G76G) has been classified 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001215.4. 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
	CA6	NM_001215.4	MANE Select	c.226G>A	p.Gly76Arg	missense	Exon 2 of 8	NP_001206.2	P23280-1
	CA6	NM_001270500.2		c.226G>A	p.Gly76Arg	missense	Exon 2 of 8	NP_001257429.1	P23280-2
	CA6	NM_001270501.2		c.79+3444G>A		intron	N/A	NP_001257430.1	P23280-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA6	ENST00000377443.7	TSL:1 MANE Select	c.226G>A	p.Gly76Arg	missense	Exon 2 of 8	ENSP00000366662.2	P23280-1
	CA6	ENST00000377436.6	TSL:1	c.226G>A	p.Gly76Arg	missense	Exon 2 of 8	ENSP00000366654.3	P23280-2
	CA6	ENST00000480186.7	TSL:2	c.226G>A	p.Gly76Arg	missense	Exon 2 of 3	ENSP00000435280.1	Q8N4G4

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

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111572

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.11
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.6
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.33
Sift	Benign	0.12	T
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.46		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
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

hg19: chr1-9009468; COSMIC: COSV66263150;