X-15628116-T-C

Variant names:

• chrX-15628116-T-C
• rs1477455320
• NM_020665.6:c.524A>G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_020665.6(CLTRN):​c.524A>G​(p.Glu175Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,091,111 control chromosomes in the GnomAD database, including 1 homozygotes. There are 9 hemizygotes 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000026 (1 hom. 8 hem.)
• Consequence: CLTRN NM_020665.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.20

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]

ENSG00000285602 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059186965).
• BP6: Variant X-15628116-T-C is Benign according to our data. Variant chrX-15628116-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2461903.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLTRN	NM_020665.6	c.524A>G	p.Glu175Gly	missense_variant	Exon 6 of 6	ENST00000380342.4	NP_065716.1
CLTRN	XM_017029680.2	c.368A>G	p.Glu123Gly	missense_variant	Exon 6 of 6		XP_016885169.1
CLTRN	XM_024452411.2	c.368A>G	p.Glu123Gly	missense_variant	Exon 6 of 6		XP_024308179.1
CLTRN	XM_017029681.2	c.215A>G	p.Glu72Gly	missense_variant	Exon 4 of 4		XP_016885170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLTRN	ENST00000380342.4	c.524A>G	p.Glu175Gly	missense_variant	Exon 6 of 6	1	NM_020665.6	ENSP00000369699.3
ENSG00000285602	ENST00000649243.1	n.356+11446A>G		intron_variant	Intron 5 of 19			ENSP00000497489.1
CLTRN	ENST00000650271.1	c.368A>G	p.Glu123Gly	missense_variant	Exon 7 of 7			ENSP00000497814.1

Frequencies

GnomAD3 genomes AF: 0.0000447 AC: 5 AN: 111923 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34079

Gnomad AFR AF: 0.0000325

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: 0.0000752

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000255 AC: 25 AN: 979136 Hom.: 1 Cov.: 28 AF XY: 0.0000267 AC XY: 8 AN XY: 299608

Gnomad4 AFR exome AF: 0.0000890

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: 0.0000283

Gnomad4 OTH exome AF: 0.0000247

GnomAD4 genome AF: 0.0000536 AC: 6 AN: 111975 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34141

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000752

Gnomad4 OTH AF: 0.000664

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000302

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 07, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.1
DANN	Benign	0.49
DEOGEN2	Benign	0.13	T;.
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.060	N;.
REVEL	Benign	0.12
Sift	Benign	0.47	T;.
Sift4G	Benign	0.42	T;.
Polyphen		0.0	B;.
Vest4		0.050
MutPred		0.35		Loss of solvent accessibility (P = 0.0387);.;
MVP		0.29
MPC		0.011
ClinPred		0.0055	T
GERP RS		-2.7
Varity_R		0.031
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs1477455320; hg19: chrX-15646239;