chr10-99732646-T-G

Variant names:

• chr10-99732646-T-G
• rs2281636
• NM_015960.3:c.61+237T>G

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.160
• Publications: 19 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CUTC	NM_015960.3	c.61+237T>G		intron_variant	Intron 1 of 8	ENST00000370476.10	NP_057044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUTC	ENST00000370476.10	c.61+237T>G		intron_variant	Intron 1 of 8	1	NM_015960.3	ENSP00000359507.5
CUTC	ENST00000471520.5	n.61+237T>G		intron_variant	Intron 1 of 7	1		ENSP00000433900.1
CUTC	ENST00000370472.4	c.-129+86T>G		intron_variant	Intron 1 of 7	5		ENSP00000359503.4
CUTC	ENST00000493385.5	n.310-3600T>G		intron_variant	Intron 2 of 4	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

African (AFR) AF: 0.462 AC: 12441 AN: 26910

American (AMR) AF: 0.643 AC: 10672 AN: 16600

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 12821 AN: 18274

East Asian (EAS) AF: 0.404 AC: 13119 AN: 32446

South Asian (SAS) AF: 0.684 AC: 41134 AN: 60154

European-Finnish (FIN) AF: 0.574 AC: 16998 AN: 29614

Middle Eastern (MID) AF: 0.719 AC: 2512 AN: 3492

European-Non Finnish (NFE) AF: 0.584 AC: 596365 AN: 1020372

Other (OTH) AF: 0.573 AC: 29902 AN: 52174

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

African (AFR) AF: 0.456 AC: 18929 AN: 41494

American (AMR) AF: 0.618 AC: 9439 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2361 AN: 3472

East Asian (EAS) AF: 0.387 AC: 1998 AN: 5158

South Asian (SAS) AF: 0.675 AC: 3251 AN: 4816

European-Finnish (FIN) AF: 0.571 AC: 6035 AN: 10564

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39844 AN: 67974

Other (OTH) AF: 0.590 AC: 1245 AN: 2110

Alfa AF: 0.582 Hom.: 93217

Bravo AF: 0.550

Asia WGS AF: 0.538 AC: 1872 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Leigh syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.5
DANN	Benign	0.51
PhyloP100		0.16
PromoterAI		0.025	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2281636; hg19: chr10-101492403;