X-15659092-C-A

Variant names:

• chrX-15659092-C-A
• NM_020665.6:c.127G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020665.6(CLTRN):​c.127G>T​(p.Asp43Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: CLTRN NM_020665.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31
• Publications: 0 publications found

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

ENSG00000285602 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

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.127G>T	p.Asp43Tyr	missense	Exon 3 of 6	NP_065716.1	Q9HBJ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLTRN	ENST00000380342.4	TSL:1 MANE Select	c.127G>T	p.Asp43Tyr	missense	Exon 3 of 6	ENSP00000369699.3	Q9HBJ8
	ENSG00000285602	ENST00000649243.1		n.-30G>T		non_coding_transcript_exon	Exon 3 of 20	ENSP00000497489.1	A0A3B3IT09
	ENSG00000285602	ENST00000649243.1		n.-30G>T		5_prime_UTR	Exon 3 of 20	ENSP00000497489.1	A0A3B3IT09

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.50	D
PhyloP100		2.3
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.37		Loss of relative solvent accessibility (P = 0.0676)
MVP		0.48
MPC		0.062
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.68
gMVP		0.64
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chrX-15677215;