rs2274333

Variant names:

• chr1-8957145-A-G
• rs2274333
• NM_001215.4:c.268A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001215.4(CA6):​c.268A>G​(p.Ser90Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,607,150 control chromosomes in the GnomAD database, including 80,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (6383 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74142 hom.)
• Consequence: CA6 NM_001215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.137
• Publications: 74 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3385882E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA6	NM_001215.4	c.268A>G	p.Ser90Gly	missense_variant	Exon 3 of 8	ENST00000377443.7	NP_001206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA6	ENST00000377443.7	c.268A>G	p.Ser90Gly	missense_variant	Exon 3 of 8	1	NM_001215.4	ENSP00000366662.2

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41696 AN: 151900 Hom.: 6376 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.290

GnomAD2 exomes AF: 0.336 AC: 82849 AN: 246652 AF XY: 0.338

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.433

Gnomad ASJ exome AF: 0.312

Gnomad EAS exome AF: 0.557

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.323

GnomAD4 exome AF: 0.313 AC: 455196 AN: 1455132 Hom.: 74142 Cov.: 33 AF XY: 0.316 AC XY: 228563 AN XY: 723228

African (AFR) AF: 0.146 AC: 4887 AN: 33364

American (AMR) AF: 0.427 AC: 18841 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 7869 AN: 25820

East Asian (EAS) AF: 0.534 AC: 21128 AN: 39562

South Asian (SAS) AF: 0.409 AC: 34998 AN: 85552

European-Finnish (FIN) AF: 0.260 AC: 13828 AN: 53196

Middle Eastern (MID) AF: 0.390 AC: 2241 AN: 5742

European-Non Finnish (NFE) AF: 0.300 AC: 332342 AN: 1107716

Other (OTH) AF: 0.318 AC: 19062 AN: 60024

GnomAD4 genome AF: 0.274 AC: 41721 AN: 152018 Hom.: 6383 Cov.: 32 AF XY: 0.278 AC XY: 20634 AN XY: 74282

African (AFR) AF: 0.152 AC: 6321 AN: 41494

American (AMR) AF: 0.351 AC: 5356 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1035 AN: 3468

East Asian (EAS) AF: 0.555 AC: 2859 AN: 5152

South Asian (SAS) AF: 0.420 AC: 2024 AN: 4824

European-Finnish (FIN) AF: 0.258 AC: 2721 AN: 10552

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20448 AN: 67950

Other (OTH) AF: 0.289 AC: 608 AN: 2102

Alfa AF: 0.298 Hom.: 21161

Bravo AF: 0.279

TwinsUK AF: 0.287 AC: 1065

ALSPAC AF: 0.303 AC: 1168

ESP6500AA AF: 0.159 AC: 701

ESP6500EA AF: 0.296 AC: 2548

ExAC AF: 0.325 AC: 39447

Asia WGS AF: 0.449 AC: 1562 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.58	T;D;D;D
MetaRNN	Benign	0.00023	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	.;M;M;.
PhyloP100		0.14
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Benign	0.17
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.085	T;T;T;T
Polyphen		0.97	.;D;.;.
Vest4		0.095, 0.086, 0.13
MPC		0.38
ClinPred		0.017	T
GERP RS		-0.41
Varity_R		0.21
gMVP		0.53
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

dbSNP: rs2274333; hg19: chr1-9017204; COSMIC: COSV107496726; COSMIC: COSV107496726;