rs3740165

Variant names:

• chr10-16907551-T-C
• rs3740165
• NM_001081.4:c.7662A>G

Variant summary

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

The NM_001081.4(CUBN):​c.7662A>G​(p.Pro2554Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 1,614,024 control chromosomes in the GnomAD database, including 3,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (864 hom., cov: 32)
  • Exomes 𝑓: 0.042 (2139 hom.)
• Consequence: CUBN NM_001081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.727

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=-0.59).
• BP6: Variant 10-16907551-T-C is Benign according to our data. Variant chr10-16907551-T-C is described in ClinVar as [Benign]. Clinvar id is 299420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.727 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.7662A>G	p.Pro2554Pro	synonymous_variant	Exon 49 of 67	ENST00000377833.10	NP_001072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.7662A>G	p.Pro2554Pro	synonymous_variant	Exon 49 of 67	1	NM_001081.4	ENSP00000367064.4
CUBN	ENST00000648092.1	n.198A>G		non_coding_transcript_exon_variant	Exon 1 of 4
CUBN	ENST00000649933.1	n.67+129A>G		intron_variant	Intron 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0816 AC: 12417 AN: 152118 Hom.: 860 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0402

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.0559

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0348

Gnomad OTH AF: 0.0722

GnomAD3 exomes AF: 0.0539 AC: 13551 AN: 251476 Hom.: 619 AF XY: 0.0506 AC XY: 6880 AN XY: 135916

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.0281

Gnomad ASJ exome AF: 0.0395

Gnomad EAS exome AF: 0.133

Gnomad SAS exome AF: 0.0486

Gnomad FIN exome AF: 0.0363

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0451

GnomAD4 exome AF: 0.0421 AC: 61554 AN: 1461788 Hom.: 2139 Cov.: 33 AF XY: 0.0417 AC XY: 30288 AN XY: 727202

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.0305

Gnomad4 ASJ exome AF: 0.0403

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.0456

Gnomad4 FIN exome AF: 0.0352

Gnomad4 NFE exome AF: 0.0331

Gnomad4 OTH exome AF: 0.0536

GnomAD4 genome AF: 0.0818 AC: 12450 AN: 152236 Hom.: 864 Cov.: 32 AF XY: 0.0809 AC XY: 6024 AN XY: 74446

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.0401

Gnomad4 ASJ AF: 0.0418

Gnomad4 EAS AF: 0.139

Gnomad4 SAS AF: 0.0562

Gnomad4 FIN AF: 0.0350

Gnomad4 NFE AF: 0.0348

Gnomad4 OTH AF: 0.0747

Alfa AF: 0.0542 Hom.: 144

Bravo AF: 0.0875

Asia WGS AF: 0.107 AC: 371 AN: 3478

EpiCase AF: 0.0370

EpiControl AF: 0.0405

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Imerslund-Grasbeck syndrome type 1 Benign:1

Jan 13, 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. -

Imerslund-Grasbeck syndrome Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.012
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3740165; hg19: chr10-16949550; COSMIC: COSV64716462;