7-151064203-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003040.4(SLC4A2):c.53C>T(p.Pro18Leu) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: SLC4A2 NM_003040.4 missense, splice_region
• Scores: Splicing: ADA: 0.004354
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.05

Genes affected

SLC4A2 (HGNC:11028): (solute carrier family 4 member 2) This gene encodes a member of the anion exchanger family of membrane transport proteins. The encoded protein regulates intracellular pH, biliary bicarbonate secretion, and chloride uptake. Reduced expression of this gene may be associated with primary biliary cirrhosis (PBC) in human patients, while differential expression of this gene may be associated with malignant hepatocellular carcinoma, colon and gastric cancers. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC4A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.34082687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A2	NM_003040.4	c.53C>T	p.Pro18Leu	missense_variant, splice_region_variant	3/23	ENST00000413384.7
SLC4A2	NM_001199692.3	c.53C>T	p.Pro18Leu	missense_variant, splice_region_variant	3/23
SLC4A2	NM_001199693.1	c.26C>T	p.Pro9Leu	missense_variant, splice_region_variant	2/22
SLC4A2	NM_001199694.2	c.11C>T	p.Pro4Leu	missense_variant, splice_region_variant	2/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A2	ENST00000413384.7	c.53C>T	p.Pro18Leu	missense_variant, splice_region_variant	3/23	1	NM_003040.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Martin Pollak Laboratory, Beth Israel Deaconess Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	25
Dann	Benign	0.89
DEOGEN2	Benign	0.013	T;T;T;T;.;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T;.;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;D;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;T;D
Polyphen		0.96, 0.98	.;D;D;.;.;.;.;.;D
Vest4		0.20, 0.20, 0.19
MutPred		0.12		Loss of relative solvent accessibility (P = 0.0414);Loss of relative solvent accessibility (P = 0.0414);Loss of relative solvent accessibility (P = 0.0414);Loss of relative solvent accessibility (P = 0.0414);Loss of relative solvent accessibility (P = 0.0414);Loss of relative solvent accessibility (P = 0.0414);Loss of relative solvent accessibility (P = 0.0414);.;.;
MVP		0.46
MPC		0.51
ClinPred		0.33	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0044
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907524; hg19: chr7-150761290;