dbSNP rs2147192747: CLTRN:p.Asp216Tyr (chrX-15627994-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020665.6(CLTRN):c.646G>T(p.Asp216Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000107 in 936,141 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D216N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000011 ( 0 hom. 1 hem. )

Consequence

CLTRN
NM_020665.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.33

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.646G>T	p.Asp216Tyr	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.646G>T	p.Asp216Tyr	missense	Exon 6 of 6	ENSP00000369699.3	Q9HBJ8
ENSG00000285602	ENST00000649243.1		n.356+11568G>T		intron	N/A	ENSP00000497489.1	A0A3B3IT09
CLTRN	ENST00000918250.1		c.646G>T	p.Asp216Tyr	missense	Exon 7 of 7	ENSP00000588309.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000107

AC:

AN:

936141

Hom.:

Cov.:

AF XY:

0.00000343

AC XY:

AN XY:

291337

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20956

American (AMR)

AF:

0.00

AC:

AN:

18561

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14217

East Asian (EAS)

AF:

0.00

AC:

AN:

24706

South Asian (SAS)

AF:

0.00

AC:

AN:

28211

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3512

European-Non Finnish (NFE)

AF:

0.00000133

AC:

AN:

753261

Other (OTH)

AF:

0.00

AC:

AN:

38147

Age Distribution

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.56

PhyloP100

1.3

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.96

Vest4

0.25

MutPred

0.37

Loss of disorder (P = 0.0014)

MVP

0.64

MPC

0.066

ClinPred

0.99

GERP RS

5.0

Varity_R

0.90

gMVP

0.67

Mutation Taster

=72/28

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over