10-16824374-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 0.349

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
CUBN	NM_001081.4	c.*601A>G		3_prime_UTR_variant	67/67	ENST00000377833.10
CUBN	XM_011519709.3	c.*601A>G		3_prime_UTR_variant	41/41
CUBN	XM_011519710.3	c.*601A>G		3_prime_UTR_variant	41/41
CUBN	XM_011519711.4	c.*601A>G		3_prime_UTR_variant	40/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.*601A>G		3_prime_UTR_variant	67/67	1	NM_001081.4	P1

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

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.444

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.679

Gnomad4 SAS exome AF: 0.279

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.352

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

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.418

Gnomad4 ASJ AF: 0.249

Gnomad4 EAS AF: 0.752

Gnomad4 SAS AF: 0.383

Gnomad4 FIN AF: 0.465

Gnomad4 NFE AF: 0.306

Gnomad4 OTH AF: 0.300

Alfa AF: 0.320 Hom.: 4101

Bravo AF: 0.337

Asia WGS AF: 0.556 AC: 1930 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.8
Dann	Benign	0.81

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: rs780635; hg19: chr10-16866373;