18-45627114-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007163.4(SLC14A2):c.488C>T(p.Ser163Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,828 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC14A2 NM_007163.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25

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]

LOC105372093 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC14A2	NM_007163.4	c.488C>T	p.Ser163Leu	missense_variant	4/20	ENST00000255226.11
LOC105372093	XR_935423.3	n.1207+9709G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC14A2	ENST00000255226.11	c.488C>T	p.Ser163Leu	missense_variant	4/20	1	NM_007163.4	P1
SLC14A2	ENST00000586448.5	c.488C>T	p.Ser163Leu	missense_variant	5/21	2		P1
SLC14A2	ENST00000323329.3	c.488C>T	p.Ser163Leu	missense_variant, NMD_transcript_variant	4/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251408 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135872

Gnomad AFR exome AF: 0.0000615

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461828 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000597

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.488C>T (p.S163L) alteration is located in exon 4 (coding exon 3) of the SLC14A2 gene. This alteration results from a C to T substitution at nucleotide position 488, causing the serine (S) at amino acid position 163 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	Uncertain	0.48
BayesDel_addAF	Benign	-0.0058	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.80
MutPred		0.81		Loss of catalytic residue at S163 (P = 0.0094);Loss of catalytic residue at S163 (P = 0.0094);
MVP		0.77
MPC		0.37
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.82
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760368681; hg19: chr18-43207079;