X-15659082-T-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_020665.6(CLTRN):c.137A>T(p.Glu46Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,166,953 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000015 ( 0 hom. 6 hem. )

Consequence

CLTRN
NM_020665.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.26

Variant links:

Genes affected

CLTRN (HGNC:29437): (collectrin, amino acid transport regulator) This gene encodes a type 1 transmembrane protein that is important for trafficking amino acid transporters to the apical brush border of proximal tubules. The encoded protein binds to amino acid transporters and regulates their expression on the plasma membrane. It also plays a role in controlling insulin exocytosis by regulating formation of the SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor) complex in pancreatic beta cells. The extracellular domain of the encoded protein may be cleaved and shed from the plasma membrane specifically in pancreatic beta cells. [provided by RefSeq, Jun 2013]

CLTRN links:

ENSG00000285602 (HGNC:):

ENSG00000285602 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLTRN	NM_020665.6 link	c.137A>T	p.Glu46Val	missense_variant	Exon 3 of 6	ENST00000380342.4	NP_065716.1	Q9HBJ8
CLTRN	XM_017029681.2 link	c.137A>T	p.Glu46Val	missense_variant	Exon 3 of 4		XP_016885170.1
CLTRN	XM_017029680.2 link	c.-20A>T		5_prime_UTR_variant	Exon 3 of 6		XP_016885169.1	A0A3B3ITM8
CLTRN	XM_024452411.2 link	c.-20A>T		5_prime_UTR_variant	Exon 3 of 6		XP_024308179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLTRN	ENST00000380342.4 link	c.137A>T	p.Glu46Val	missense_variant	Exon 3 of 6	1	NM_020665.6	ENSP00000369699.3	Q9HBJ8
ENSG00000285602	ENST00000649243.1 link	n.-20A>T		non_coding_transcript_exon_variant	Exon 3 of 20			ENSP00000497489.1	A0A3B3IT09
ENSG00000285602	ENST00000649243.1 link	n.-20A>T		5_prime_UTR_variant	Exon 3 of 20			ENSP00000497489.1	A0A3B3IT09
CLTRN	ENST00000650271.1 link	c.-20A>T		5_prime_UTR_variant	Exon 4 of 7			ENSP00000497814.1	A0A3B3ITM8

Frequencies

GnomAD3 genomes

AF:

0.00000906

AC:

AN:

110372

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32586

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:

0.00424

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1056529

Hom.:

Cov.:

AF XY:

0.0000182

AC XY:

AN XY:

329767

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000906

AC:

AN:

110424

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32648

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.137A>T (p.E46V) alteration is located in exon 3 (coding exon 3) of the TMEM27 gene. This alteration results from a A to T substitution at nucleotide position 137, causing the glutamic acid (E) at amino acid position 46 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autism

Uncertain:1

Centre for Addiction & Mental Health, Centre for Addiction & Mental Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Gene not previously associated with disease; independent supportng evidence needed -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.72

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

0.93

Vest4

0.90

MutPred

0.52

Gain of sheet (P = 0.0827);

MVP

0.62

MPC

0.058

ClinPred

0.99

GERP RS

5.7

Varity_R

0.85

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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