2-64989708-C-T

Position:

chr2-64989708-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003038.5(SLC1A4):c.65C>T(p.Pro22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000859 in 1,517,486 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P22H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00087 ( 2 hom. )

Consequence

SLC1A4
NM_003038.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.209

Variant links:

Genes affected

SLC1A4 (HGNC:10942): (solute carrier family 1 member 4) The protein encoded by this gene is a sodium-dependent neutral amino acid transporter for alanine, serine, cysteine, and threonine. Defects in this gene have been associated with developmental delay, microcephaly, and intellectual disability. [provided by RefSeq, Jan 2017]

SLC1A4 links:

LINC02245 (HGNC:53134): (long intergenic non-protein coding RNA 2245)

LINC02245 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048915446).

BP6

Variant 2-64989708-C-T is Benign according to our data. Variant chr2-64989708-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 624135.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000871 (1189/1365304) while in subpopulation MID AF= 0.00937 (37/3950). AF 95% confidence interval is 0.00699. There are 2 homozygotes in gnomad4_exome. There are 610 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC1A4	NM_003038.5 linkuse as main transcript	c.65C>T	p.Pro22Leu	missense_variant	1/8	ENST00000234256.4
SLC1A4	NM_001193493.2 linkuse as main transcript	c.-134+1088C>T		intron_variant
SLC1A4	NM_001348406.2 linkuse as main transcript	c.-134+1088C>T		intron_variant
SLC1A4	NM_001348407.2 linkuse as main transcript	c.-134+1154C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A4	ENST00000234256.4 linkuse as main transcript	c.65C>T	p.Pro22Leu	missense_variant	1/8	1	NM_003038.5	P1	P43007-1
LINC02245	ENST00000653778.1 linkuse as main transcript	n.513+58246G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00114

AC:

156

AN:

136516

Hom.:

AF XY:

0.00124

AC XY:

AN XY:

78204

show subpopulations

Gnomad AFR exome

AF:

0.000200

Gnomad AMR exome

AF:

0.00112

Gnomad ASJ exome

AF:

0.00799

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000916

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000861

Gnomad OTH exome

AF:

0.00331

GnomAD4 exome

AF:

0.000871

AC:

1189

AN:

1365304

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

610

AN XY:

677624

show subpopulations

Gnomad4 AFR exome

AF:

0.000581

Gnomad4 AMR exome

AF:

0.00135

Gnomad4 ASJ exome

AF:

0.00741

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000886

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000741

Gnomad4 OTH exome

AF:

0.00117

GnomAD4 genome

AF:

0.000756

AC:

115

AN:

152182

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.000790

ESP6500AA

AF:

0.000263

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000746

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -

SLC1A4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.66

M_CAP

Benign

0.085

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.81

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.95

REVEL

Benign

0.065

Sift

Benign

0.081

Sift4G

Benign

0.34

Polyphen

0.10

Vest4

0.14

MVP

0.52

MPC

1.4

ClinPred

0.034

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.047

gMVP

0.31

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

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