NM_001039960.3:c.2141C>G

Variant names:

• chr12-51475175-C-G
• rs749911186
• NM_001039960.3:c.2141C>G

Variant summary

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

The NM_001039960.3(SLC4A8):​c.2141C>G​(p.Thr714Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. T714M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC4A8 NM_001039960.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.983
• Publications: 3 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.2141C>G	p.Thr714Arg	missense	Exon 16 of 25	NP_001035049.1	Q2Y0W8-1
	SLC4A8	NM_001405270.1		c.2105C>G	p.Thr702Arg	missense	Exon 16 of 25	NP_001392199.1
	SLC4A8	NM_001258401.3		c.1982C>G	p.Thr661Arg	missense	Exon 16 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.2141C>G	p.Thr714Arg	missense	Exon 16 of 25	ENSP00000405812.2	Q2Y0W8-1
	SLC4A8	ENST00000358657.7	TSL:1	c.1982C>G	p.Thr661Arg	missense	Exon 16 of 25	ENSP00000351483.4	Q2Y0W8-5
	SLC4A8	ENST00000514353.7	TSL:1	c.1982C>G	p.Thr661Arg	missense	Exon 16 of 17	ENSP00000442561.2	Q2Y0W8-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.030
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.98
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.46	N
REVEL	Uncertain	0.33
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.30	B
Vest4		0.36
MutPred		0.44		Gain of MoRF binding (P = 0.0201)
MVP		0.12
MPC		0.99
ClinPred		0.67	D
GERP RS		5.6
Varity_R		0.15
gMVP		0.76
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: 31

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

Other links and lift over

dbSNP: rs749911186; hg19: chr12-51868959;