rs74375025

Variant names:

• chr10-16905665-G-A
• rs74375025
• NM_001081.4:c.7912+538C>T

Variant summary

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

The NM_001081.4(CUBN):​c.7912+538C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0807 in 152,228 control chromosomes in the GnomAD database, including 581 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 0.081 (581 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 9 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

ENSG00000296126 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001081.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	NM_001081.4	MANE Select	c.7912+538C>T		intron	N/A	NP_001072.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.7912+538C>T		intron	N/A	ENSP00000367064.4
	CUBN	ENST00000648092.1		n.448+538C>T		intron	N/A
	CUBN	ENST00000649933.1		n.274+538C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0807 AC: 12278 AN: 152110 Hom.: 579 Cov.: 32

Gnomad AFR AF: 0.0357

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.0767

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0804

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0923

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

GnomAD4 genome AF: 0.0807 AC: 12280 AN: 152228 Hom.: 581 Cov.: 32 AF XY: 0.0794 AC XY: 5905 AN XY: 74414

African (AFR) AF: 0.0359 AC: 1490 AN: 41540

American (AMR) AF: 0.0766 AC: 1171 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 504 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5178

South Asian (SAS) AF: 0.114 AC: 551 AN: 4820

European-Finnish (FIN) AF: 0.0804 AC: 852 AN: 10594

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7278 AN: 68012

Other (OTH) AF: 0.0903 AC: 191 AN: 2114

Alfa AF: 0.0929 Hom.: 101

Bravo AF: 0.0771

Asia WGS AF: 0.0580 AC: 205 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.84
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74375025; hg19: chr10-16947664;