10-16824374-T-C

Variant names:

• chr10-16824374-T-C
• rs780635
• NM_001081.4:c.*601A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001081.4(CUBN):​c.*601A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 153,896 control chromosomes in the GnomAD database, including 9,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9651 hom., cov: 32)
  • Exomes 𝑓: 0.34 (125 hom.)
• Consequence: CUBN NM_001081.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.349
• Publications: 9 publications found

Genes affected

CUBN (HGNC:2548): (cubilin) Cubilin (CUBN) acts as a receptor for intrinsic factor-vitamin B12 complexes. The role of receptor is supported by the presence of 27 CUB domains. Cubulin is located within the epithelium of intestine and kidney. Mutations in CUBN may play a role in autosomal recessive megaloblastic anemia. [provided by RefSeq, Jul 2008]

CUBN Gene-Disease associations (from GenCC):

• Imerslund-Grasbeck syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• proteinuria, chronic benign

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Imerslund-Grasbeck syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-16824374-T-C is Benign according to our data. Variant chr10-16824374-T-C is described in ClinVar as [Benign]. Clinvar id is 299330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.*601A>G		3_prime_UTR_variant	Exon 67 of 67	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3	c.*601A>G		3_prime_UTR_variant	Exon 41 of 41		XP_011518011.1
CUBN	XM_011519710.3	c.*601A>G		3_prime_UTR_variant	Exon 41 of 41		XP_011518012.1
CUBN	XM_011519711.4	c.*601A>G		3_prime_UTR_variant	Exon 40 of 40		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.*601A>G		3_prime_UTR_variant	Exon 67 of 67	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.342 AC: 52007 AN: 151900 Hom.: 9626 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.292

GnomAD4 exome AF: 0.337 AC: 633 AN: 1878 Hom.: 125 Cov.: 0 AF XY: 0.337 AC XY: 326 AN XY: 968

African (AFR) AF: 0.250 AC: 2 AN: 8

American (AMR) AF: 0.444 AC: 151 AN: 340

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 1 AN: 10

East Asian (EAS) AF: 0.679 AC: 19 AN: 28

South Asian (SAS) AF: 0.279 AC: 39 AN: 140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.310 AC: 401 AN: 1294

Other (OTH) AF: 0.352 AC: 19 AN: 54

GnomAD4 genome AF: 0.343 AC: 52068 AN: 152018 Hom.: 9651 Cov.: 32 AF XY: 0.355 AC XY: 26364 AN XY: 74312

African (AFR) AF: 0.297 AC: 12308 AN: 41480

American (AMR) AF: 0.418 AC: 6391 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3470

East Asian (EAS) AF: 0.752 AC: 3894 AN: 5178

South Asian (SAS) AF: 0.383 AC: 1850 AN: 4826

European-Finnish (FIN) AF: 0.465 AC: 4896 AN: 10534

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20801 AN: 67944

Other (OTH) AF: 0.300 AC: 633 AN: 2112

Alfa AF: 0.325 Hom.: 5630

Bravo AF: 0.337

Asia WGS AF: 0.556 AC: 1930 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1 Benign:1

Jan 12, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.8
DANN	Benign	0.81
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs780635; hg19: chr10-16866373;