rs2273737

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUBN	NM_001081.4	c.489+35A>T		intron_variant		ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.489+35A>T		intron_variant			XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.489+35A>T		intron_variant		1	NM_001081.4	ENSP00000367064.4
CUBN	ENST00000433666.5	c.150+35A>T		intron_variant		5		ENSP00000415970.1
CUBN	ENST00000377823.1	n.563A>T		non_coding_transcript_exon_variant	5/5	3

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

GnomAD3 exomes AF: 0.00776 AC: 1871 AN: 241072 Hom.: 31 AF XY: 0.00950 AC XY: 1232 AN XY: 129642

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 SAS exome AF: 0.0281

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

Gnomad4 AFR exome AF: 0.000624

Gnomad4 AMR exome AF: 0.00167

Gnomad4 ASJ exome AF: 0.0126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0287

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.00368

Gnomad4 OTH exome AF: 0.00565

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

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.00404

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000568 Hom.: 802

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.8
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs2273737; hg19: chr10-17165552;