dbSNP rs774193816: SLC5A6:p.Gln622ArgfsTer51 (chr2-27200477-CCT-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_021095.4(SLC5A6):c.1865_1866delAG(p.Gln622ArgfsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

SLC5A6
NM_021095.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.197

Variant links:

Genes affected

SLC5A6 (HGNC:11041): (solute carrier family 5 member 6) Enables biotin transmembrane transporter activity and pantothenate transmembrane transporter activity. Involved in anion transmembrane transport and transport across blood-brain barrier. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC5A6 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0225 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-27200477-CCT-C is Pathogenic according to our data. Variant chr2-27200477-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1341577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A6	NM_021095.4 link	c.1865_1866delAG	p.Gln622ArgfsTer51	frameshift_variant	Exon 17 of 17	ENST00000310574.8	NP_066918.2	Q9Y289Q9HD19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC5A6	ENST00000310574.8 link	c.1865_1866delAG	p.Gln622ArgfsTer51	frameshift_variant	Exon 17 of 17	1	NM_021095.4	ENSP00000310208.3	Q9Y289
SLC5A6	ENST00000408041.5 link	c.1865_1866delAG	p.Gln622ArgfsTer14	frameshift_variant	Exon 18 of 18	1		ENSP00000384853.1	Q9Y289
SLC5A6	ENST00000461757.1 link	n.1415_1416delAG		non_coding_transcript_exon_variant	Exon 3 of 3	2
SLC5A6	ENST00000488743.6 link	n.2551_2552delAG		non_coding_transcript_exon_variant	Exon 16 of 17	2

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250398

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135306

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000708

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1461734

Hom.:

AF XY:

0.0000399

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000549

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000966

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000718

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodegeneration, infantile-onset, biotin-responsive

Pathogenic:3

Jun 02, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 01, 2021

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Oct 13, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein extension as the last 14 amino acids are replaced with 50 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 31392107, 35217562) -

Peripheral motor neuropathy, childhood-onset, biotin-responsive

Pathogenic:1

Feb 08, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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