Genetic Variant NM_020665.6:c.644A>G (chrX-15627996-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020665.6(CLTRN):c.644A>G(p.Glu215Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,049,799 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000053 ( 0 hom. 0 hem. )

Consequence

CLTRN
NM_020665.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.81

Publications

0 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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09269422).

BS2

High Hemizygotes in GnomAd4 at 2 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.644A>G	p.Glu215Gly	missense	Exon 6 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.644A>G	p.Glu215Gly	missense	Exon 6 of 6	ENSP00000369699.3	Q9HBJ8
ENSG00000285602	ENST00000649243.1		n.356+11566A>G		intron	N/A	ENSP00000497489.1	A0A3B3IT09
CLTRN	ENST00000918250.1		c.644A>G	p.Glu215Gly	missense	Exon 7 of 7	ENSP00000588309.1

Frequencies

GnomAD3 genomes

AF:

0.0000535

AC:

AN:

112101

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000195

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000178

AC:

AN:

112598

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000220

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000533

AC:

AN:

937698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

291760

show subpopulations

African (AFR)

AF:

0.000238

AC:

AN:

20976

American (AMR)

AF:

0.00

AC:

AN:

18649

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14327

East Asian (EAS)

AF:

0.00

AC:

AN:

24740

South Asian (SAS)

AF:

0.00

AC:

AN:

28518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34663

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3514

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

754113

Other (OTH)

AF:

0.00

AC:

AN:

38198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000535

AC:

AN:

112101

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

34241

show subpopulations

African (AFR)

AF:

0.000195

AC:

AN:

30829

American (AMR)

AF:

0.00

AC:

AN:

10557

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3586

South Asian (SAS)

AF:

0.00

AC:

AN:

2714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6103

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53228

Other (OTH)

AF:

0.00

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000712

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.00000825

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

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.63

M_CAP

Benign

0.0070

MetaRNN

Benign

0.093

MetaSVM

Benign

-1.0

PhyloP100

2.8

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

REVEL

Benign

0.049

Sift

Benign

0.39

Sift4G

Benign

0.21

Polyphen

0.0020

Vest4

0.17

MVP

0.42

MPC

0.012

ClinPred

0.12

GERP RS

4.7

Varity_R

0.14

gMVP

0.17

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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