1-8949323-A-T

Variant names:

• chr1-8949323-A-T
• rs1472002957
• NM_001215.4:c.140A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001215.4(CA6):​c.140A>T​(p.Gln47Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q47R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CA6 NM_001215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.18
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA6	NM_001215.4	MANE Select	c.140A>T	p.Gln47Leu	missense	Exon 2 of 8	NP_001206.2	P23280-1
	CA6	NM_001270500.2		c.140A>T	p.Gln47Leu	missense	Exon 2 of 8	NP_001257429.1	P23280-2
	CA6	NM_001270501.2		c.79+3358A>T		intron	N/A	NP_001257430.1	P23280-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA6	ENST00000377443.7	TSL:1 MANE Select	c.140A>T	p.Gln47Leu	missense	Exon 2 of 8	ENSP00000366662.2	P23280-1
	CA6	ENST00000377436.6	TSL:1	c.140A>T	p.Gln47Leu	missense	Exon 2 of 8	ENSP00000366654.3	P23280-2
	CA6	ENST00000480186.7	TSL:2	c.140A>T	p.Gln47Leu	missense	Exon 2 of 3	ENSP00000435280.1	Q8N4G4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250478 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		8.2
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.96		Loss of disorder (P = 0.0308)
MVP		0.93
MPC		0.64
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.97
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs1472002957; hg19: chr1-9009382;