rs12246329

Positions:

• chr10-17017463-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001081.4(CUBN):​c.4168+2370G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 152,022 control chromosomes in the GnomAD database, including 3,555 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3555 hom., cov: 31)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.194

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.4168+2370G>A		intron_variant		ENST00000377833.10
CUBN	XM_011519708.3	c.4168+2370G>A		intron_variant
CUBN	XM_011519709.3	c.154+2370G>A		intron_variant
CUBN	XM_011519710.3	c.130+2370G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.4168+2370G>A		intron_variant		1	NM_001081.4	P1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29942 AN: 151904 Hom.: 3551 Cov.: 31

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0663

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.181

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.197 AC: 29975 AN: 152022 Hom.: 3555 Cov.: 31 AF XY: 0.196 AC XY: 14578 AN XY: 74304

Gnomad4 AFR AF: 0.338

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.0665

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.186

Alfa AF: 0.152 Hom.: 2454

Bravo AF: 0.198

Asia WGS AF: 0.158 AC: 549 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.7
DANN	Benign	0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs12246329; hg19: chr10-17059462;