1-8949347-C-T

Variant names:

• chr1-8949347-C-T
• rs2274327
• NM_001215.4:c.164C>T

Variant summary

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

The NM_001215.4(CA6):​c.164C>T​(p.Thr55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,611,070 control chromosomes in the GnomAD database, including 117,752 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.32 (9002 hom., cov: 33)
  • Exomes 𝑓: 0.38 (108750 hom.)
• Consequence: CA6 NM_001215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.241

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=7.671118E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA6	NM_001215.4	c.164C>T	p.Thr55Met	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.164C>T	p.Thr55Met	missense_variant	Exon 2 of 8	1	NM_001215.4	ENSP00000366662.2
CA6	ENST00000480186.7	c.164C>T	p.Thr55Met	missense_variant	Exon 2 of 3	2		ENSP00000435280.1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48697 AN: 151908 Hom.: 9004 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.534

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.525

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.367

GnomAD3 exomes AF: 0.357 AC: 89130 AN: 249486 Hom.: 17108 AF XY: 0.361 AC XY: 48773 AN XY: 134926

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.507

Gnomad EAS exome AF: 0.249

Gnomad SAS exome AF: 0.280

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.380 AC: 554810 AN: 1459044 Hom.: 108750 Cov.: 33 AF XY: 0.378 AC XY: 274518 AN XY: 725892

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.323

Gnomad4 ASJ exome AF: 0.507

Gnomad4 EAS exome AF: 0.241

Gnomad4 SAS exome AF: 0.276

Gnomad4 FIN exome AF: 0.459

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.377

GnomAD4 genome AF: 0.320 AC: 48702 AN: 152026 Hom.: 9002 Cov.: 33 AF XY: 0.323 AC XY: 24000 AN XY: 74342

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.348

Gnomad4 ASJ AF: 0.525

Gnomad4 EAS AF: 0.254

Gnomad4 SAS AF: 0.281

Gnomad4 FIN AF: 0.467

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.367

Alfa AF: 0.387 Hom.: 28081

Bravo AF: 0.307

TwinsUK AF: 0.395 AC: 1465

ALSPAC AF: 0.395 AC: 1521

ESP6500AA AF: 0.144 AC: 635

ESP6500EA AF: 0.414 AC: 3559

ExAC AF: 0.354 AC: 42929

Asia WGS AF: 0.294 AC: 1022 AN: 3478

EpiCase AF: 0.408

EpiControl AF: 0.419

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	.;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.40	T;T;T;T
MetaRNN	Benign	0.00077	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;.;L;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.27	N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.10	T;D;T;D
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.99	.;.;D;.
Vest4		0.073, 0.098, 0.10
MPC		0.55
ClinPred		0.066	T
GERP RS		-7.7
Varity_R		0.037
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2274327; hg19: chr1-9009406; COSMIC: COSV66262569;