rs1801229

Variant names:

• chr10-16982616-A-T
• rs1801229
• NM_001081.4:c.4563T>A

Your query was ambiguous. Multiple possible variants found:

• chr10-16982616-A-T
• chr10-16982616-A-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001081.4(CUBN):​c.4563T>A​(p.Ile1521Ile) 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 NM_001081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.65
• Publications: 17 publications found

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]

CUBN Gene-Disease associations (from GenCC):

• Imerslund-Grasbeck syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• proteinuria, chronic benign

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Imerslund-Grasbeck syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 299480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001081.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	NM_001081.4	MANE Select	c.4563T>A	p.Ile1521Ile	synonymous	Exon 31 of 67	NP_001072.2	O60494

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.4563T>A	p.Ile1521Ile	synonymous	Exon 31 of 67	ENSP00000367064.4	O60494
	CUBN	ENST00000438254.1	TSL:3	n.129T>A		non_coding_transcript_exon	Exon 2 of 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

GnomAD2 exomes AF: 0.770 AC: 193439 AN: 251130 AF XY: 0.789

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 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

African (AFR) AF: 0.437 AC: 14610 AN: 33460

American (AMR) AF: 0.574 AC: 25656 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 21581 AN: 26126

East Asian (EAS) AF: 0.501 AC: 19894 AN: 39678

South Asian (SAS) AF: 0.796 AC: 68646 AN: 86218

European-Finnish (FIN) AF: 0.854 AC: 45521 AN: 53302

Middle Eastern (MID) AF: 0.815 AC: 4695 AN: 5764

European-Non Finnish (NFE) AF: 0.900 AC: 999504 AN: 1111122

Other (OTH) AF: 0.824 AC: 49715 AN: 60350

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

African (AFR) AF: 0.456 AC: 18900 AN: 41446

American (AMR) AF: 0.701 AC: 10712 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 2863 AN: 3470

East Asian (EAS) AF: 0.533 AC: 2746 AN: 5154

South Asian (SAS) AF: 0.786 AC: 3780 AN: 4812

European-Finnish (FIN) AF: 0.851 AC: 9020 AN: 10600

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.893 AC: 60735 AN: 67982

Other (OTH) AF: 0.768 AC: 1620 AN: 2110

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Imerslund-Grasbeck syndrome type 1 (2)
-	-	2	not provided (2)
-	-	1	Imerslund-Grasbeck syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.1
DANN	Benign	0.78
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801229; hg19: chr10-17024615; COSMIC: COSV108229690;