rs12249562

Positions:

• chr10-16973406-G-A
• chr10-16973406-G-T

Variant summary

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

The NM_001081.4(CUBN):​c.4695+9078C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 152,124 control chromosomes in the GnomAD database, including 2,323 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 0.17 (2323 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.387

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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.4695+9078C>T		intron_variant		ENST00000377833.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.4695+9078C>T		intron_variant		1	NM_001081.4	P1
CUBN	ENST00000438254.1	n.262-7429C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25739 AN: 152006 Hom.: 2322 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.162

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

GnomAD4 genome AF: 0.169 AC: 25754 AN: 152124 Hom.: 2323 Cov.: 32 AF XY: 0.169 AC XY: 12544 AN XY: 74374

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.198

Gnomad4 OTH AF: 0.159

Alfa AF: 0.186 Hom.: 732

Bravo AF: 0.159

Asia WGS AF: 0.103 AC: 359 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.9
DANN	Benign	0.59

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: rs12249562; hg19: chr10-17015405;