rs150309054

Positions:

• chr10-17110971-G-A
• chr10-17110971-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001081.4(CUBN):​c.963C>T​(p.Pro321=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,194 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (12 hom.)
• Consequence: CUBN NM_001081.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.717

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=-0.81).
• BP6: Variant 10-17110971-G-A is Benign according to our data. Variant chr10-17110971-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 299532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.717 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00568 (865/152326) while in subpopulation AFR AF= 0.0185 (769/41564). AF 95% confidence interval is 0.0174. There are 3 homozygotes in gnomad4. There are 407 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.963C>T	p.Pro321=	synonymous_variant	9/67	ENST00000377833.10
CUBN	XM_011519708.3	c.963C>T	p.Pro321=	synonymous_variant	9/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.963C>T	p.Pro321=	synonymous_variant	9/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes AF: 0.00569 AC: 866 AN: 152208 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00171 AC: 430 AN: 251394 Hom.: 6 AF XY: 0.00122 AC XY: 166 AN XY: 135870

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000798 AC: 1166 AN: 1461868 Hom.: 12 Cov.: 33 AF XY: 0.000704 AC XY: 512 AN XY: 727238

Gnomad4 AFR exome AF: 0.0199

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00568 AC: 865 AN: 152326 Hom.: 3 Cov.: 33 AF XY: 0.00547 AC XY: 407 AN XY: 74468

Gnomad4 AFR AF: 0.0185

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00304 Hom.: 0

Bravo AF: 0.00631

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 10, 2023	- -

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. -

Imerslund-Grasbeck syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.9
DANN	Benign	0.77

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: rs150309054; hg19: chr10-17152970; COSMIC: COSV64721408;