chr1-8949385-A-C

Variant names:

• chr1-8949385-A-C
• rs2274328
• NM_001215.4:c.202A>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001215.4(CA6):​c.202A>C​(p.Met68Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 1,609,992 control chromosomes in the GnomAD database, including 205,038 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.51 (20013 hom., cov: 32)
  • Exomes 𝑓: 0.50 (185025 hom.)
• Consequence: CA6 NM_001215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.643

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.3160733E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA6	NM_001215.4	c.202A>C	p.Met68Leu	missense_variant	Exon 2 of 8	ENST00000377443.7	NP_001206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA6	ENST00000377443.7	c.202A>C	p.Met68Leu	missense_variant	Exon 2 of 8	1	NM_001215.4	ENSP00000366662.2
CA6	ENST00000480186.7	c.202A>C	p.Met68Leu	missense_variant	Exon 2 of 3	2		ENSP00000435280.1

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77517 AN: 151838 Hom.: 20003 Cov.: 32

Gnomad AFR AF: 0.532

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.648

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.521

GnomAD3 exomes AF: 0.489 AC: 121952 AN: 249386 Hom.: 30318 AF XY: 0.492 AC XY: 66323 AN XY: 134896

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.623

Gnomad EAS exome AF: 0.427

Gnomad SAS exome AF: 0.453

Gnomad FIN exome AF: 0.546

Gnomad NFE exome AF: 0.510

Gnomad OTH exome AF: 0.513

GnomAD4 exome AF: 0.502 AC: 731328 AN: 1458036 Hom.: 185025 Cov.: 37 AF XY: 0.500 AC XY: 362859 AN XY: 725450

Gnomad4 AFR exome AF: 0.525

Gnomad4 AMR exome AF: 0.391

Gnomad4 ASJ exome AF: 0.626

Gnomad4 EAS exome AF: 0.434

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.540

Gnomad4 NFE exome AF: 0.506

Gnomad4 OTH exome AF: 0.514

GnomAD4 genome AF: 0.510 AC: 77559 AN: 151956 Hom.: 20013 Cov.: 32 AF XY: 0.509 AC XY: 37845 AN XY: 74284

Gnomad4 AFR AF: 0.532

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.648

Gnomad4 EAS AF: 0.429

Gnomad4 SAS AF: 0.448

Gnomad4 FIN AF: 0.548

Gnomad4 NFE AF: 0.505

Gnomad4 OTH AF: 0.521

Alfa AF: 0.515 Hom.: 51833

Bravo AF: 0.505

TwinsUK AF: 0.510 AC: 1890

ALSPAC AF: 0.516 AC: 1988

ESP6500AA AF: 0.545 AC: 2403

ESP6500EA AF: 0.524 AC: 4505

ExAC AF: 0.490 AC: 59480

Asia WGS AF: 0.480 AC: 1667 AN: 3478

EpiCase AF: 0.522

EpiControl AF: 0.525

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.14
DANN	Benign	0.30
DEOGEN2	Benign	0.0048	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.28	T;T;T
MetaRNN	Benign	0.000033	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.3	.;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.77	N;N;N
REVEL	Benign	0.093
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.049
MutPred		0.24		Loss of MoRF binding (P = 0.0766);Loss of MoRF binding (P = 0.0766);Loss of MoRF binding (P = 0.0766);
MPC		0.14
ClinPred		0.0014	T
GERP RS		2.4
Varity_R		0.17
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs2274328; hg19: chr1-9009444; COSMIC: COSV66261772;