rs141937843

chr10-16831397-G-Achr10-16831397-G-Cchr10-16831397-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.10383C>T(p.Ser3461=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,888 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (22 hom.)
• Consequence: CUBN NM_001081.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.00900

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=-0.78).
• BP6: Variant 10-16831397-G-A is Benign according to our data. Variant chr10-16831397-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 299360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-16831397-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.009 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00388 (591/152314) while in subpopulation AFR AF= 0.00963 (400/41558). AF 95% confidence interval is 0.00885. There are 0 homozygotes in gnomad4. There are 275 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.10383C>T	p.Ser3461=	synonymous_variant	65/67	ENST00000377833.10
CUBN	XM_011519709.3	c.6369C>T	p.Ser2123=	synonymous_variant	39/41
CUBN	XM_011519710.3	c.6345C>T	p.Ser2115=	synonymous_variant	39/41
CUBN	XM_011519711.4	c.6225C>T	p.Ser2075=	synonymous_variant	38/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.10383C>T	p.Ser3461=	synonymous_variant	65/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 592 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000852

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00238 AC: 599 AN: 251346 Hom.: 7 AF XY: 0.00222 AC XY: 301 AN XY: 135840

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00164 AC: 2395 AN: 1461574 Hom.: 22 Cov.: 31 AF XY: 0.00160 AC XY: 1162 AN XY: 727110

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.0221

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000892

Gnomad4 OTH exome AF: 0.00414

GnomAD4 genome AF: 0.00388 AC: 591 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00369 AC XY: 275 AN XY: 74484

Gnomad4 AFR AF: 0.00963

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00331 Hom.: 2

Bravo AF: 0.00473

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CUBN: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Imerslund-Grasbeck syndrome type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

CUBN-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 23, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Imerslund-Grasbeck syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	3.6
Dann	Benign	0.64

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: rs141937843; hg19: chr10-16873396;