X-15639585-T-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020665.6(CLTRN):c.489A>T(p.Leu163Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,676 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

CLTRN
NM_020665.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.04

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.064080596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLTRN	NM_020665.6 link	c.489A>T	p.Leu163Phe	missense_variant	Exon 5 of 6	ENST00000380342.4	NP_065716.1	Q9HBJ8
CLTRN	XM_017029680.2 link	c.333A>T	p.Leu111Phe	missense_variant	Exon 5 of 6		XP_016885169.1	A0A3B3ITM8
CLTRN	XM_024452411.2 link	c.333A>T	p.Leu111Phe	missense_variant	Exon 5 of 6		XP_024308179.1
CLTRN	XM_017029681.2 link	c.204-11458A>T		intron_variant	Intron 3 of 3		XP_016885170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLTRN	ENST00000380342.4 link	c.489A>T	p.Leu163Phe	missense_variant	Exon 5 of 6	1	NM_020665.6	ENSP00000369699.3	Q9HBJ8
ENSG00000285602	ENST00000649243.1 link	n.333A>T		non_coding_transcript_exon_variant	Exon 5 of 20			ENSP00000497489.1	A0A3B3IT09
CLTRN	ENST00000650271.1 link	c.333A>T	p.Leu111Phe	missense_variant	Exon 6 of 7			ENSP00000497814.1	A0A3B3ITM8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000561

AC:

AN:

178372

Hom.:

AF XY:

0.00

AC XY:

AN XY:

63274

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.14e-7

AC:

AN:

1094676

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360352

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.489A>T (p.L163F) alteration is located in exon 5 (coding exon 5) of the TMEM27 gene. This alteration results from a A to T substitution at nucleotide position 489, causing the leucine (L) at amino acid position 163 to be replaced by a phenylalanine (F). 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

Benign

0.067

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.50

CADD

Benign

8.2

DANN

Benign

0.93

DEOGEN2

Benign

0.14

T;.

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.064

T;T

MetaSVM

Benign

-0.80

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.57

N;.

REVEL

Benign

0.10

Sift

Benign

0.55

T;.

Sift4G

Benign

0.17

T;.

Polyphen

0.34

B;.

Vest4

0.18

MutPred

0.33

Loss of catalytic residue at L163 (P = 0.0492);.;

MVP

0.58

MPC

0.025

ClinPred

0.11

GERP RS

-2.0

Varity_R

0.10

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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