10-16833193-A-T

Variant names:

• chr10-16833193-A-T
• rs4088454
• NM_001081.4:c.10363-1776T>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.10363-1776T>A 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 1,098 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 (1098 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.625
• Publications: 2 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 = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.10363-1776T>A		intron_variant	Intron 64 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3	c.6349-1776T>A		intron_variant	Intron 38 of 40		XP_011518011.1
CUBN	XM_011519710.3	c.6325-1776T>A		intron_variant	Intron 38 of 40		XP_011518012.1
CUBN	XM_011519711.4	c.6205-1776T>A		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.10363-1776T>A		intron_variant	Intron 64 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16919 AN: 152050 Hom.: 1091 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.0541

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0817

Gnomad OTH AF: 0.0942

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

GnomAD4 genome AF: 0.111 AC: 16942 AN: 152168 Hom.: 1098 Cov.: 32 AF XY: 0.114 AC XY: 8444 AN XY: 74390

African (AFR) AF: 0.167 AC: 6951 AN: 41502

American (AMR) AF: 0.0540 AC: 826 AN: 15286

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

East Asian (EAS) AF: 0.148 AC: 764 AN: 5166

South Asian (SAS) AF: 0.133 AC: 642 AN: 4824

European-Finnish (FIN) AF: 0.159 AC: 1682 AN: 10590

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0817 AC: 5557 AN: 68012

Other (OTH) AF: 0.101 AC: 214 AN: 2114

Alfa AF: 0.0473 Hom.: 50

Bravo AF: 0.106

Asia WGS AF: 0.162 AC: 561 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	0.39
DANN	Benign	0.66
PhyloP100		-0.63
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: rs4088454; hg19: chr10-16875192;