rs2281636

Positions:

• chr10-99732646-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015960.3(CUTC):​c.61+237T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,412,112 control chromosomes in the GnomAD database, including 240,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23487 hom., cov: 32)
  • Exomes 𝑓: 0.58 (216610 hom.)
• Consequence: CUTC NM_015960.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.160

Genes affected

CUTC (HGNC:24271): (cutC copper transporter) Members of the CUT family of copper transporters are associated with copper homeostasis and are involved in the uptake, storage, delivery, and efflux of copper (Gupta et al., 1995 [PubMed 7635807]; Li et al., 2005 [PubMed 16182249]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-99732646-T-G is Benign according to our data. Variant chr10-99732646-T-G is described in ClinVar as [Benign]. Clinvar id is 298434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUTC	NM_015960.3	c.61+237T>G		intron_variant		ENST00000370476.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUTC	ENST00000370476.10	c.61+237T>G		intron_variant		1	NM_015960.3	P1
CUTC	ENST00000471520.5	c.61+237T>G		intron_variant, NMD_transcript_variant		1
CUTC	ENST00000370472.4	c.-129+86T>G		intron_variant		5
CUTC	ENST00000493385.5	n.310-3600T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83777 AN: 151960 Hom.: 23481 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.539

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.590

GnomAD4 exome AF: 0.584 AC: 735964 AN: 1260036 Hom.: 216610 AF XY: 0.587 AC XY: 358097 AN XY: 609676

Gnomad4 AFR exome AF: 0.462

Gnomad4 AMR exome AF: 0.643

Gnomad4 ASJ exome AF: 0.702

Gnomad4 EAS exome AF: 0.404

Gnomad4 SAS exome AF: 0.684

Gnomad4 FIN exome AF: 0.574

Gnomad4 NFE exome AF: 0.584

Gnomad4 OTH exome AF: 0.573

GnomAD4 genome AF: 0.551 AC: 83796 AN: 152076 Hom.: 23487 Cov.: 32 AF XY: 0.552 AC XY: 41032 AN XY: 74314

Gnomad4 AFR AF: 0.456

Gnomad4 AMR AF: 0.618

Gnomad4 ASJ AF: 0.680

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.675

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.586

Gnomad4 OTH AF: 0.590

Alfa AF: 0.589 Hom.: 46667

Bravo AF: 0.550

Asia WGS AF: 0.538 AC: 1872 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.5
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2281636; hg19: chr10-101492403;