12-51474379-A-G

Variant names:

• chr12-51474379-A-G
• rs199981470
• NM_001039960.3:c.1942A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001039960.3(SLC4A8):​c.1942A>G​(p.Thr648Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,308 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T648S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC4A8 NM_001039960.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.12
• Publications: 0 publications found

Genes affected

SLC4A8 (HGNC:11034): (solute carrier family 4 member 8) The protein encoded by this gene is a membrane protein that functions to transport sodium and bicarbonate ions across the cell membrane. The encoded protein is important for pH regulation in neurons. The activity of this protein can be inhibited by 4,4'-Di-isothiocyanatostilbene-2,2'-disulfonic acid (DIDS). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

SLC4A8 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039960.3. 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
	SLC4A8	NM_001039960.3	MANE Select	c.1942A>G	p.Thr648Ala	missense	Exon 15 of 25	NP_001035049.1	Q2Y0W8-1
	SLC4A8	NM_001405270.1		c.1906A>G	p.Thr636Ala	missense	Exon 15 of 25	NP_001392199.1
	SLC4A8	NM_001258401.3		c.1783A>G	p.Thr595Ala	missense	Exon 15 of 25	NP_001245330.1	Q2Y0W8-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A8	ENST00000453097.7	TSL:1 MANE Select	c.1942A>G	p.Thr648Ala	missense	Exon 15 of 25	ENSP00000405812.2	Q2Y0W8-1
	SLC4A8	ENST00000358657.7	TSL:1	c.1783A>G	p.Thr595Ala	missense	Exon 15 of 25	ENSP00000351483.4	Q2Y0W8-5
	SLC4A8	ENST00000514353.7	TSL:1	c.1783A>G	p.Thr595Ala	missense	Exon 15 of 17	ENSP00000442561.2	Q2Y0W8-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250874 AF XY: 0.00000738

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448308 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718414

⚠️ 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: 33300

American (AMR) AF: 0.00 AC: 0 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39378

South Asian (SAS) AF: 0.00 AC: 0 AN: 85152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101422

Other (OTH) AF: 0.00 AC: 0 AN: 59712

⚠️ 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	0.27
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.021	D
Sift4G	Benign	0.12	T
Polyphen		0.64	P
Vest4		0.69
MutPred		0.44		Loss of ubiquitination at K653 (P = 0.0787)
MVP		0.13
MPC		1.1
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.16
gMVP		0.87
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs199981470; hg19: chr12-51868163;