chr2-219628015-C-T

Variant names:

• chr2-219628015-C-T
• rs897296053
• NM_005070.4:c.23C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005070.4(SLC4A3):​c.23C>T​(p.Pro8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SLC4A3 NM_005070.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.720
• Publications: 0 publications found

Genes affected

SLC4A3 (HGNC:11029): (solute carrier family 4 member 3) The protein encoded by this gene is a plasma membrane anion exchange protein. The encoded protein has been found in brain, heart, kidney, small intestine, and lung. [provided by RefSeq, May 2016]

SLC4A3 Gene-Disease associations (from GenCC):

• short QT syndrome 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: G2P, ClinGen
• autosomal dominant distal renal tubular acidosis

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox

ENSG00000228973 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38228944).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005070.4. 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
	SLC4A3	NM_005070.4	MANE Select	c.23C>T	p.Pro8Leu	missense	Exon 2 of 23	NP_005061.3	P48751-1
	SLC4A3	NM_001326559.2		c.23C>T	p.Pro8Leu	missense	Exon 2 of 23	NP_001313488.2	P48751-3
	SLC4A3	NM_201574.3		c.23C>T	p.Pro8Leu	missense	Exon 2 of 23	NP_963868.3	P48751-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A3	ENST00000358055.8	TSL:1 MANE Select	c.23C>T	p.Pro8Leu	missense	Exon 2 of 23	ENSP00000350756.3	P48751-1
	SLC4A3	ENST00000273063.10	TSL:1	c.23C>T	p.Pro8Leu	missense	Exon 2 of 23	ENSP00000273063.6	P48751-3
	SLC4A3	ENST00000425141.5	TSL:1	n.23C>T		non_coding_transcript_exon	Exon 2 of 23	ENSP00000396863.1	F8WD49

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436810 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 714134

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

African (AFR) AF: 0.0000313 AC: 1 AN: 31984

American (AMR) AF: 0.00 AC: 0 AN: 41192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25068

East Asian (EAS) AF: 0.00 AC: 0 AN: 37842

South Asian (SAS) AF: 0.00 AC: 0 AN: 83630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4652

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102082

Other (OTH) AF: 0.00 AC: 0 AN: 59092

⚠️ 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.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.0056	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.72
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.060	T
Polyphen		1.0	D
Vest4		0.28
MutPred		0.25		Loss of glycosylation at P8 (P = 0.0517)
MVP		0.81
ClinPred		0.87	D
GERP RS		3.2
PromoterAI		-0.092	Neutral
Varity_R		0.11
gMVP		0.31
Mutation Taster		=83/17	polymorphism

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: rs897296053; hg19: chr2-220492737;