10-16982616-A-T

Position:

• chr10-16982616-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000377833.10(CUBN):​c.4563T>A​(p.Ile1521=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,612,786 control chromosomes in the GnomAD database, including 587,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (43738 hom., cov: 32)
  • Exomes 𝑓: 0.86 (544048 hom.)
• Consequence: CUBN ENST00000377833.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.65

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 10-16982616-A-T is Benign according to our data. Variant chr10-16982616-A-T is described in ClinVar as [Benign]. Clinvar id is 299480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-16982616-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUBN	NM_001081.4	c.4563T>A	p.Ile1521=	synonymous_variant	31/67	ENST00000377833.10	NP_001072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.4563T>A	p.Ile1521=	synonymous_variant	31/67	1	NM_001081.4	ENSP00000367064	P1
CUBN	ENST00000438254.1	n.129T>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111487 AN: 151936 Hom.: 43739 Cov.: 32

Gnomad AFR AF: 0.456

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.785

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.893

Gnomad OTH AF: 0.767

GnomAD3 exomes AF: 0.770 AC: 193439 AN: 251130 Hom.: 77805 AF XY: 0.789 AC XY: 107124 AN XY: 135726

Gnomad AFR exome AF: 0.447

Gnomad AMR exome AF: 0.559

Gnomad ASJ exome AF: 0.824

Gnomad EAS exome AF: 0.541

Gnomad SAS exome AF: 0.793

Gnomad FIN exome AF: 0.850

Gnomad NFE exome AF: 0.889

Gnomad OTH exome AF: 0.815

GnomAD4 exome AF: 0.856 AC: 1249822 AN: 1460732 Hom.: 544048 Cov.: 45 AF XY: 0.857 AC XY: 622493 AN XY: 726774

Gnomad4 AFR exome AF: 0.437

Gnomad4 AMR exome AF: 0.574

Gnomad4 ASJ exome AF: 0.826

Gnomad4 EAS exome AF: 0.501

Gnomad4 SAS exome AF: 0.796

Gnomad4 FIN exome AF: 0.854

Gnomad4 NFE exome AF: 0.900

Gnomad4 OTH exome AF: 0.824

GnomAD4 genome AF: 0.733 AC: 111518 AN: 152054 Hom.: 43738 Cov.: 32 AF XY: 0.731 AC XY: 54309 AN XY: 74326

Gnomad4 AFR AF: 0.456

Gnomad4 AMR AF: 0.701

Gnomad4 ASJ AF: 0.825

Gnomad4 EAS AF: 0.533

Gnomad4 SAS AF: 0.786

Gnomad4 FIN AF: 0.851

Gnomad4 NFE AF: 0.893

Gnomad4 OTH AF: 0.768

Alfa AF: 0.840 Hom.: 17739

Bravo AF: 0.703

Asia WGS AF: 0.661 AC: 2303 AN: 3478

EpiCase AF: 0.887

EpiControl AF: 0.888

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Imerslund-Grasbeck syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.1
DANN	Benign	0.78

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: rs1801229; hg19: chr10-17024615;