rs12146414

Variant names:

• chr10-17026252-A-G
• rs12146414
• NM_001081.4:c.4018-6269T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001081.4(CUBN):​c.4018-6269T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 152,238 control chromosomes in the GnomAD database, including 1,561 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 0.12 (1561 hom., cov: 33)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.234
• Publications: 6 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.4018-6269T>C		intron_variant	Intron 27 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.4018-6269T>C		intron_variant	Intron 27 of 54		XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.4018-6269T>C		intron_variant	Intron 27 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18852 AN: 152120 Hom.: 1551 Cov.: 33

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0865

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0786

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.111

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

GnomAD4 genome AF: 0.124 AC: 18897 AN: 152238 Hom.: 1561 Cov.: 33 AF XY: 0.122 AC XY: 9086 AN XY: 74442

African (AFR) AF: 0.229 AC: 9518 AN: 41514

American (AMR) AF: 0.0863 AC: 1321 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3468

East Asian (EAS) AF: 0.0205 AC: 106 AN: 5176

South Asian (SAS) AF: 0.117 AC: 564 AN: 4826

European-Finnish (FIN) AF: 0.0786 AC: 834 AN: 10614

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.0833 AC: 5668 AN: 68024

Other (OTH) AF: 0.116 AC: 245 AN: 2112

Alfa AF: 0.0994 Hom.: 1696

Bravo AF: 0.128

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.68
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12146414; hg19: chr10-17068251;