rs12146414

Positions:

• chr10-17026252-A-G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.85).
• 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/exons	MANE	Protein	UniProt
CUBN	NM_001081.4	c.4018-6269T>C		intron_variant		ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.4018-6269T>C		intron_variant			XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.4018-6269T>C		intron_variant		1	NM_001081.4	ENSP00000367064	P1

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

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.0863

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.0205

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.0786

Gnomad4 NFE AF: 0.0833

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0955 Hom.: 1079

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs12146414; hg19: chr10-17068251;