Genetic Variant NM_001215.4:c.730G>T (chr1-8970867-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001215.4(CA6):c.730G>T(p.Val244Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CA6
NM_001215.4 missense, splice_region

Scores

Splicing: ADA: 0.9770

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.364

Publications

0 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:

ENSG00000290109 (HGNC:):

ENSG00000290109 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CA6	NM_001215.4	MANE Select	c.730G>T	p.Val244Phe	missense splice_region	Exon 7 of 8	NP_001206.2	P23280-1
CA6	NM_001270500.2		c.730G>T	p.Val244Phe	missense splice_region	Exon 7 of 8	NP_001257429.1	P23280-2
CA6	NM_001270501.2		c.550G>T	p.Val184Phe	missense splice_region	Exon 6 of 7	NP_001257430.1	P23280-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CA6	ENST00000377443.7	TSL:1 MANE Select	c.730G>T	p.Val244Phe	missense splice_region	Exon 7 of 8	ENSP00000366662.2	P23280-1
CA6	ENST00000377436.6	TSL:1	c.730G>T	p.Val244Phe	missense splice_region	Exon 7 of 8	ENSP00000366654.3	P23280-2
CA6	ENST00000377442.3	TSL:1	c.550G>T	p.Val184Phe	missense splice_region	Exon 6 of 7	ENSP00000366661.2	P23280-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251470

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1450164

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33268

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.00

AC:

AN:

85954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1101522

Other (OTH)

AF:

0.0000167

AC:

AN:

59936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.27

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.056

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.7

PhyloP100

-0.36

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.33

Sift

Benign

0.10

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.45

MutPred

0.73

Gain of ubiquitination at K246 (P = 0.0837)

MVP

0.77

MPC

0.72

ClinPred

0.50

GERP RS

-6.0

Varity_R

0.39

gMVP

0.80

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.73

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.38

Position offset: -39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over