NM_006996.3:c.796G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006996.3(SLC19A2):c.796G>A(p.Val266Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,658 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0069 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 8 hom. )

Consequence

SLC19A2
NM_006996.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -2.48

Publications

5 publications found

Variant links:

Genes affected

SLC19A2 (HGNC:10938): (solute carrier family 19 member 2) This gene encodes the thiamin transporter protein. Mutations in this gene cause thiamin-responsive megaloblastic anemia syndrome (TRMA), which is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anemia and sensorineural deafness. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

SLC19A2 Gene-Disease associations (from GenCC):

thiamine-responsive megaloblastic anemia syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Orphanet

SLC19A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035036802).

BP6

Variant 1-169477166-C-T is Benign according to our data. Variant chr1-169477166-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 293525.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00692 (1054/152288) while in subpopulation AFR AF = 0.024 (996/41538). AF 95% confidence interval is 0.0227. There are 12 homozygotes in GnomAd4. There are 532 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006996.3. 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
	SLC19A2	NM_006996.3	MANE Select	c.796G>A	p.Val266Met	missense	Exon 2 of 6	NP_008927.1	O60779-1
	SLC19A2	NM_001319667.1		c.205-6980G>A		intron	N/A	NP_001306596.1	A0A024R8Y5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC19A2	ENST00000236137.10	TSL:1 MANE Select	c.796G>A	p.Val266Met	missense	Exon 2 of 6	ENSP00000236137.5	O60779-1
SLC19A2	ENST00000367804.4	TSL:1	c.205-6980G>A		intron	N/A	ENSP00000356778.3	O60779-2
SLC19A2	ENST00000646596.1		c.796G>A	p.Val266Met	missense	Exon 2 of 6	ENSP00000494404.1	A0A2R8Y5B5

Frequencies

GnomAD3 genomes

AF:

0.00689

AC:

1049

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00190

AC:

477

AN:

250962

AF XY:

0.00164

show subpopulations

Gnomad AFR exome

AF:

0.0250

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000687

AC:

1004

AN:

1461370

Hom.:

Cov.:

AF XY:

0.000607

AC XY:

441

AN XY:

727016

show subpopulations

African (AFR)

AF:

0.0212

AC:

711

AN:

33460

American (AMR)

AF:

0.00152

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00164

AC:

AN:

5484

European-Non Finnish (NFE)

AF:

0.000115

AC:

128

AN:

1111882

Other (OTH)

AF:

0.00136

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

120

179

239

299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00692

AC:

1054

AN:

152288

Hom.:

Cov.:

AF XY:

0.00714

AC XY:

532

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0240

AC:

996

AN:

41538

American (AMR)

AF:

0.00222

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68030

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

142

190

237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00289

Hom.:

Bravo

AF:

0.00796

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0247

AC:

109

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00231

AC:

281

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness (1)

Monogenic diabetes (1)

not provided (1)

Thiamine-responsive megaloblastic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.0020

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.25

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.30

MetaRNN

Benign

0.0035

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.49

PhyloP100

-2.5

PrimateAI

Benign

0.22

PROVEAN

Benign

0.0

REVEL

Benign

0.26

Sift

Benign

0.14

Sift4G

Benign

0.14

Polyphen

0.0020

Vest4

0.13

MVP

0.32

MPC

0.17

ClinPred

0.0065

GERP RS

-11

Varity_R

0.021

gMVP

0.15

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over