rs11254238

Variant names:

• chr10-16832243-A-C
• rs11254238
• NM_001081.4:c.10363-826T>G

Variant summary

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

The NM_001081.4(CUBN):​c.10363-826T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,168 control chromosomes in the GnomAD database, including 1,076 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 0.11 (1076 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.10363-826T>G		intron_variant	Intron 64 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3	c.6349-826T>G		intron_variant	Intron 38 of 40		XP_011518011.1
CUBN	XM_011519710.3	c.6325-826T>G		intron_variant	Intron 38 of 40		XP_011518012.1
CUBN	XM_011519711.4	c.6205-826T>G		intron_variant	Intron 37 of 39		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.10363-826T>G		intron_variant	Intron 64 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16933 AN: 152050 Hom.: 1066 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.0539

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0819

Gnomad OTH AF: 0.0910

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

GnomAD4 genome AF: 0.111 AC: 16963 AN: 152168 Hom.: 1076 Cov.: 32 AF XY: 0.114 AC XY: 8463 AN XY: 74398

African (AFR) AF: 0.168 AC: 6977 AN: 41502

American (AMR) AF: 0.0538 AC: 823 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3470

East Asian (EAS) AF: 0.148 AC: 763 AN: 5162

South Asian (SAS) AF: 0.132 AC: 635 AN: 4828

European-Finnish (FIN) AF: 0.159 AC: 1684 AN: 10598

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0819 AC: 5567 AN: 67994

Other (OTH) AF: 0.0981 AC: 207 AN: 2110

Alfa AF: 0.101 Hom.: 314

Bravo AF: 0.106

Asia WGS AF: 0.165 AC: 570 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	1.4
DANN	Benign	0.55
PhyloP100		0.12
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: rs11254238; hg19: chr10-16874242;