10-17123553-T-G

Position:

• chr10-17123553-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001081.4(CUBN):​c.489+35A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0925 in 1,452,092 control chromosomes in the GnomAD database, including 7,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (548 hom., cov: 32)
  • Exomes 𝑓: 0.095 (6907 hom.)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: 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=-0.88).
• BP6: Variant 10-17123553-T-G is Benign according to our data. Variant chr10-17123553-T-G is described in ClinVar as [Benign]. Clinvar id is 1269839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0729 AC: 11086 AN: 152158 Hom.: 551 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.0556

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.0239

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.0897

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0960

Gnomad OTH AF: 0.0707

GnomAD3 exomes AF: 0.0897 AC: 21615 AN: 241072 Hom.: 1224 AF XY: 0.0980 AC XY: 12703 AN XY: 129642

Gnomad AFR exome AF: 0.0221

Gnomad AMR exome AF: 0.0432

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.0218

Gnomad SAS exome AF: 0.193

Gnomad FIN exome AF: 0.0874

Gnomad NFE exome AF: 0.0956

Gnomad OTH exome AF: 0.0917

GnomAD4 exome AF: 0.0949 AC: 123297 AN: 1299814 Hom.: 6907 Cov.: 18 AF XY: 0.0991 AC XY: 64829 AN XY: 653992

Gnomad4 AFR exome AF: 0.0215

Gnomad4 AMR exome AF: 0.0447

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.0200

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.0908

Gnomad4 NFE exome AF: 0.0933

Gnomad4 OTH exome AF: 0.0956

GnomAD4 genome AF: 0.0727 AC: 11074 AN: 152278 Hom.: 548 Cov.: 32 AF XY: 0.0744 AC XY: 5542 AN XY: 74444

Gnomad4 AFR AF: 0.0210

Gnomad4 AMR AF: 0.0555

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.0239

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.0897

Gnomad4 NFE AF: 0.0960

Gnomad4 OTH AF: 0.0700

Alfa AF: 0.0885 Hom.: 802

Bravo AF: 0.0646

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.9
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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; COSMIC: COSV64701249;