Variant 18-45632471-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_007163.4(SLC14A2):c.643A>C(p.Met215Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

SLC14A2
NM_007163.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.55

Variant links:

Genes affected

SLC14A2 (HGNC:10919): (solute carrier family 14 member 2) The protein encoded by this gene belongs to the urea transporter family. In mammalian cells, urea is the chief end product of nitrogen catabolism, and plays an important role in the urinary concentration mechanism. This protein is expressed in the inner medulla of the kidney, and mediates rapid transepithelial urea transport across the inner medullary collecting duct. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2011]

SLC14A2 links:

LOC105372093 (HGNC:):

LOC105372093 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC14A2	NM_007163.4 linkuse as main transcript	c.643A>C	p.Met215Leu	missense_variant	5/20	ENST00000255226.11
LOC105372093	XR_935423.3 linkuse as main transcript	n.1207+4352T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC14A2	ENST00000255226.11 linkuse as main transcript	c.643A>C	p.Met215Leu	missense_variant	5/20	1	NM_007163.4	P1	Q15849-1
SLC14A2	ENST00000586448.5 linkuse as main transcript	c.643A>C	p.Met215Leu	missense_variant	6/21	2		P1	Q15849-1
SLC14A2	ENST00000323329.3 linkuse as main transcript	c.643A>C	p.Met215Leu	missense_variant, NMD_transcript_variant	5/11	2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251036

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461490

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727052

show subpopulations

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:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000487

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2023

The c.643A>C (p.M215L) alteration is located in exon 5 (coding exon 4) of the SLC14A2 gene. This alteration results from a A to C substitution at nucleotide position 643, causing the methionine (M) at amino acid position 215 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Benign

-0.60

MutationAssessor

Pathogenic

3.3

M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.65

.;N

REVEL

Benign

0.26

Sift

Benign

0.057

.;T

Sift4G

Uncertain

0.029

D;D

Polyphen

0.98

D;D

Vest4

0.67

MutPred

0.64

Loss of catalytic residue at M215 (P = 0.0222);Loss of catalytic residue at M215 (P = 0.0222);

MVP

0.51

MPC

0.084

ClinPred

0.66

GERP RS

4.5

Varity_R

0.46

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over