rs12246329

Variant names:

• chr10-17017463-C-T
• rs12246329
• NM_001081.4:c.4168+2370G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• 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 -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 rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.4168+2370G>A		intron_variant	Intron 28 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.4168+2370G>A		intron_variant	Intron 28 of 54		XP_011518010.1
CUBN	XM_011519709.3	c.154+2370G>A		intron_variant	Intron 2 of 40		XP_011518011.1
CUBN	XM_011519710.3	c.130+2370G>A		intron_variant	Intron 2 of 40		XP_011518012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.4168+2370G>A		intron_variant	Intron 28 of 66	1	NM_001081.4	ENSP00000367064.4

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

African (AFR) AF: 0.338 AC: 13976 AN: 41406

American (AMR) AF: 0.136 AC: 2078 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3466

East Asian (EAS) AF: 0.0665 AC: 344 AN: 5176

South Asian (SAS) AF: 0.198 AC: 952 AN: 4820

European-Finnish (FIN) AF: 0.167 AC: 1763 AN: 10572

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9679 AN: 67992

Other (OTH) AF: 0.186 AC: 393 AN: 2108

Alfa AF: 0.158 Hom.: 3490

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
PhyloP100		0.19
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: rs12246329; hg19: chr10-17059462;