7-151064944-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_003040.4(SLC4A2):c.556G>A(p.Ala186Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC4A2 NM_003040.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.10

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC4A2
• PP5: Variant 7-151064944-G-A is Pathogenic according to our data. Variant chr7-151064944-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2500827.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20087719).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A2	NM_003040.4	c.556G>A	p.Ala186Thr	missense_variant	5/23	ENST00000413384.7
SLC4A2	NM_001199692.3	c.556G>A	p.Ala186Thr	missense_variant	5/23
SLC4A2	NM_001199693.1	c.529G>A	p.Ala177Thr	missense_variant	4/22
SLC4A2	NM_001199694.2	c.514G>A	p.Ala172Thr	missense_variant	4/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A2	ENST00000413384.7	c.556G>A	p.Ala186Thr	missense_variant	5/23	1	NM_003040.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461118 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Osteopetrosis, autosomal recessive 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.0062	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.059	T;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	L;L;.;.
MutationTaster	Benign	0.74	N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.48	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.95	P;P;.;D
Vest4		0.24
MutPred		0.15		Gain of phosphorylation at A186 (P = 0.0082);Gain of phosphorylation at A186 (P = 0.0082);.;.;
MVP		0.72
MPC		0.55
ClinPred		0.41	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs1797182637; hg19: chr7-150762031;