2-219628517-C-T

Variant names:

• chr2-219628517-C-T
• rs1246161509
• NM_005070.4:c.164C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005070.4(SLC4A3):​c.164C>T​(p.Pro55Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,364 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SLC4A3 NM_005070.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11201206).
• BS2: High AC in GnomAd4 at 24 AD gene.

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.164C>T	p.Pro55Leu	missense	Exon 3 of 23	NP_005061.3	P48751-1
	SLC4A3	NM_001326559.2		c.164C>T	p.Pro55Leu	missense	Exon 3 of 23	NP_001313488.2	P48751-3
	SLC4A3	NM_201574.3		c.164C>T	p.Pro55Leu	missense	Exon 3 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.164C>T	p.Pro55Leu	missense	Exon 3 of 23	ENSP00000350756.3	P48751-1
	SLC4A3	ENST00000273063.10	TSL:1	c.164C>T	p.Pro55Leu	missense	Exon 3 of 23	ENSP00000273063.6	P48751-3
	SLC4A3	ENST00000425141.5	TSL:1	n.164C>T		non_coding_transcript_exon	Exon 3 of 23	ENSP00000396863.1	F8WD49

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152054 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000401 AC: 10 AN: 249538 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461310 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726974

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.000202 AC: 9 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111836

Other (OTH) AF: 0.0000166 AC: 1 AN: 60348

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152054 Hom.: 1 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74276

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00144 AC: 22 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000144

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	0.082
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Benign	0.085	T
Sift4G	Benign	0.63	T
Polyphen		0.27	B
Vest4		0.18
MutPred		0.27		Loss of catalytic residue at P54 (P = 0.0096)
MVP		0.69
ClinPred		0.069	T
GERP RS		3.9
Varity_R		0.082
gMVP		0.33
Mutation Taster		=91/9	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: rs1246161509; hg19: chr2-220493239;