X-15627994-C-T

Variant names:

• chrX-15627994-C-T
• NM_020665.6:c.646G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020665.6(CLTRN):​c.646G>A​(p.Asp216Asn) 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 936,145 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000011 (0 hom. 0 hem.)
• Consequence: CLTRN NM_020665.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28269282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLTRN	NM_020665.6	c.646G>A	p.Asp216Asn	missense_variant	Exon 6 of 6	ENST00000380342.4	NP_065716.1
CLTRN	XM_017029680.2	c.490G>A	p.Asp164Asn	missense_variant	Exon 6 of 6		XP_016885169.1
CLTRN	XM_024452411.2	c.490G>A	p.Asp164Asn	missense_variant	Exon 6 of 6		XP_024308179.1
CLTRN	XM_017029681.2	c.337G>A	p.Asp113Asn	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.646G>A	p.Asp216Asn	missense_variant	Exon 6 of 6	1	NM_020665.6	ENSP00000369699.3
ENSG00000285602	ENST00000649243.1	n.356+11568G>A		intron_variant	Intron 5 of 19			ENSP00000497489.1
CLTRN	ENST00000650271.1	c.490G>A	p.Asp164Asn	missense_variant	Exon 7 of 7			ENSP00000497814.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000107 AC: 1 AN: 936145 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 291339

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000405

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646G>A (p.D216N) alteration is located in exon 6 (coding exon 6) of the TMEM27 gene. This alteration results from a G to A substitution at nucleotide position 646, causing the aspartic acid (D) at amino acid position 216 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.71	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.86	T
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0080	D;.
Polyphen		0.0020	B;.
Vest4		0.11
MutPred		0.29		Gain of helix (P = 0.0854);.;
MVP		0.37
MPC		0.013
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.51
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-15646117;