Genetic Variant NM_020665.6:c.479T>A (chrX-15639595-A-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_020665.6(CLTRN):c.479T>A(p.Leu160Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000373 in 1,207,639 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L160L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000034 ( 0 hom. 17 hem. )

Consequence

CLTRN
NM_020665.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.91

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Hartnup disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CLTRN links:

ENSG00000285602 (HGNC:):

ENSG00000285602 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020665.6. 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
	CLTRN	NM_020665.6	MANE Select	c.479T>A	p.Leu160Gln	missense	Exon 5 of 6	NP_065716.1	Q9HBJ8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLTRN	ENST00000380342.4	TSL:1 MANE Select	c.479T>A	p.Leu160Gln	missense	Exon 5 of 6	ENSP00000369699.3	Q9HBJ8
ENSG00000285602	ENST00000649243.1		n.323T>A		non_coding_transcript_exon	Exon 5 of 20	ENSP00000497489.1	A0A3B3IT09
CLTRN	ENST00000918250.1		c.479T>A	p.Leu160Gln	missense	Exon 6 of 7	ENSP00000588309.1

Frequencies

GnomAD3 genomes

AF:

0.0000714

AC:

AN:

112019

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000285

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00422

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00133

GnomAD2 exomes

AF:

0.0000500

AC:

AN:

180079

AF XY:

0.0000463

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000338

AC:

AN:

1095567

Hom.:

Cov.:

AF XY:

0.0000471

AC XY:

AN XY:

361129

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26305

American (AMR)

AF:

0.0000860

AC:

AN:

34870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19332

East Asian (EAS)

AF:

0.00

AC:

AN:

30178

South Asian (SAS)

AF:

0.0000935

AC:

AN:

53461

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40524

Middle Eastern (MID)

AF:

0.000969

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.0000262

AC:

AN:

840741

Other (OTH)

AF:

0.0000652

AC:

AN:

46030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000714

AC:

AN:

112072

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30854

American (AMR)

AF:

0.000284

AC:

AN:

10554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3578

South Asian (SAS)

AF:

0.00

AC:

AN:

2711

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6087

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53206

Other (OTH)

AF:

0.00131

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.42

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.43

MetaSVM

Uncertain

-0.010

PhyloP100

3.9

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.50

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.058

Polyphen

0.97

Vest4

0.58

MutPred

0.43

Loss of stability (P = 0.043)

MVP

0.65

MPC

0.064

ClinPred

0.23

GERP RS

5.8

Varity_R

0.46

gMVP

0.44

Mutation Taster

=89/11

polymorphism

(source)

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

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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