10-17039154-C-T

Variant names:

• chr10-17039154-C-T
• rs11254339
• NM_001081.4:c.4017+1879G>A

Variant summary

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

The NM_001081.4(CUBN):​c.4017+1879G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,020 control chromosomes in the GnomAD database, including 5,392 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 0.22 (5392 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 8 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.4017+1879G>A		intron_variant	Intron 27 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.4017+1879G>A		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.4017+1879G>A		intron_variant	Intron 27 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33533 AN: 151902 Hom.: 5374 Cov.: 32

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.188

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

GnomAD4 genome AF: 0.221 AC: 33602 AN: 152020 Hom.: 5392 Cov.: 32 AF XY: 0.225 AC XY: 16756 AN XY: 74316

African (AFR) AF: 0.443 AC: 18319 AN: 41390

American (AMR) AF: 0.161 AC: 2459 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 465 AN: 3472

East Asian (EAS) AF: 0.275 AC: 1420 AN: 5166

South Asian (SAS) AF: 0.346 AC: 1666 AN: 4818

European-Finnish (FIN) AF: 0.180 AC: 1904 AN: 10572

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.100 AC: 6815 AN: 68010

Other (OTH) AF: 0.190 AC: 400 AN: 2108

Alfa AF: 0.141 Hom.: 8039

Bravo AF: 0.228

Asia WGS AF: 0.327 AC: 1137 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.30
DANN	Benign	0.74
PhyloP100		-1.3
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: rs11254339; hg19: chr10-17081153;