Genetic Variant CA6:p.Thr55Met (chr1-8949347-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 15/21 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 0.32 ( 9002 hom., cov: 33)

Exomes 𝑓: 0.38 ( 108750 hom. )

Consequence

CA6
NM_001215.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.241

Publications

46 publications found

Variant links:

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]

CA6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 link	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 link	c.164C>T	p.Thr55Met	missense_variant	Exon 2 of 8	1	NM_001215.4	ENSP00000366662.2
CA6	ENST00000480186.7 link	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.:

show subpopulations

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

GnomAD2 exomes

AF:

0.357

AC:

89130

AN:

249486

AF XY:

0.361

show subpopulations

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 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.:

AF XY:

0.378

AC XY:

274518

AN XY:

725892

show subpopulations

African (AFR)

AF:

0.123

AC:

4109

AN:

33362

American (AMR)

AF:

0.323

AC:

14371

AN:

44428

Ashkenazi Jewish (ASJ)

AF:

0.507

AC:

13226

AN:

26074

East Asian (EAS)

AF:

0.241

AC:

9529

AN:

39578

South Asian (SAS)

AF:

0.276

AC:

23714

AN:

86038

European-Finnish (FIN)

AF:

0.459

AC:

24489

AN:

53392

Middle Eastern (MID)

AF:

0.414

AC:

2387

AN:

5764

European-Non Finnish (NFE)

AF:

0.397

AC:

440259

AN:

1110092

Other (OTH)

AF:

0.377

AC:

22726

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

15786

31573

47359

63146

78932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13470

26940

40410

53880

67350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.320

AC:

48702

AN:

152026

Hom.:

9002

Cov.:

AF XY:

0.323

AC XY:

24000

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.136

AC:

5657

AN:

41446

American (AMR)

AF:

0.348

AC:

5322

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.525

AC:

1823

AN:

3470

East Asian (EAS)

AF:

0.254

AC:

1306

AN:

5146

South Asian (SAS)

AF:

0.281

AC:

1358

AN:

4828

European-Finnish (FIN)

AF:

0.467

AC:

4935

AN:

10564

Middle Eastern (MID)

AF:

0.473

AC:

139

AN:

294

European-Non Finnish (NFE)

AF:

0.396

AC:

26899

AN:

67976

Other (OTH)

AF:

0.367

AC:

776

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1652

3304

4955

6607

8259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.372

Hom.:

37774

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

BayesDel_noAF

Benign

-0.39

CADD

Benign

6.5

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

.;T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.40

T;T;T;T

MetaRNN

Benign

0.00077

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

.;.;L;L

PhyloP100

-0.24

PrimateAI

Benign

0.28

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

GERP RS

-7.7

Varity_R

0.037

gMVP

0.49

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over