chr1-8949385-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001215.4(CA6):​c.202A>T​(p.Met68Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CA6 NM_001215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.643
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031716287).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA6	NM_001215.4	MANE Select	c.202A>T	p.Met68Leu	missense	Exon 2 of 8	NP_001206.2
	CA6	NM_001270500.2		c.202A>T	p.Met68Leu	missense	Exon 2 of 8	NP_001257429.1
	CA6	NM_001270501.2		c.79+3420A>T		intron	N/A	NP_001257430.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA6	ENST00000377443.7	TSL:1 MANE Select	c.202A>T	p.Met68Leu	missense	Exon 2 of 8	ENSP00000366662.2
	CA6	ENST00000377436.6	TSL:1	c.202A>T	p.Met68Leu	missense	Exon 2 of 8	ENSP00000366654.3
	CA6	ENST00000480186.7	TSL:2	c.202A>T	p.Met68Leu	missense	Exon 2 of 3	ENSP00000435280.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460802 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 726738

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111406

Other (OTH) AF: 0.00 AC: 0 AN: 60358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.20
DANN	Benign	0.28
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.3	N
PhyloP100		0.64
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.049
MutPred		0.24		Loss of MoRF binding (P = 0.0766)
MVP		0.25
MPC		0.14
ClinPred		0.038	T
GERP RS		2.4
Varity_R		0.17
gMVP		0.46
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2274328; hg19: chr1-9009444;