rs2273737

Variant names:

• chr10-17123553-T-A
• rs2273737
• NM_001081.4:c.489+35A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-17123553-T-A
• chr10-17123553-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001081.4(CUBN):​c.489+35A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00553 in 1,453,020 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (72 hom.)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0780
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-17123553-T-A is Benign according to our data. Variant chr10-17123553-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1214387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00446 (679/152294) while in subpopulation SAS AF = 0.0286 (138/4820). AF 95% confidence interval is 0.0247. There are 6 homozygotes in GnomAd4. There are 396 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.489+35A>T		intron	N/A	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.489+35A>T		intron	N/A	ENSP00000367064.4	O60494
	CUBN	ENST00000433666.5	TSL:5	c.150+35A>T		intron	N/A	ENSP00000415970.1	H7C480
	CUBN	ENST00000377823.1	TSL:3	n.563A>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 680 AN: 152174 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00776 AC: 1871 AN: 241072 AF XY: 0.00950

Gnomad AFR exome AF: 0.000588

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00513

Gnomad OTH exome AF: 0.00605

GnomAD4 exome AF: 0.00565 AC: 7352 AN: 1300726 Hom.: 72 Cov.: 18 AF XY: 0.00657 AC XY: 4298 AN XY: 654446

African (AFR) AF: 0.000624 AC: 19 AN: 30468

American (AMR) AF: 0.00167 AC: 73 AN: 43622

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 315 AN: 24916

East Asian (EAS) AF: 0.00 AC: 0 AN: 38994

South Asian (SAS) AF: 0.0287 AC: 2347 AN: 81680

European-Finnish (FIN) AF: 0.0122 AC: 646 AN: 53082

Middle Eastern (MID) AF: 0.0140 AC: 77 AN: 5482

European-Non Finnish (NFE) AF: 0.00368 AC: 3564 AN: 967468

Other (OTH) AF: 0.00565 AC: 311 AN: 55014

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152294 Hom.: 6 Cov.: 32 AF XY: 0.00532 AC XY: 396 AN XY: 74456

African (AFR) AF: 0.000673 AC: 28 AN: 41584

American (AMR) AF: 0.00131 AC: 20 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0286 AC: 138 AN: 4820

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00404 AC: 275 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000364 Hom.: 1228

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.8
DANN	Benign	0.62
PhyloP100		0.078
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2273737; hg19: chr10-17165552;