10-16969176-A-G

Variant names:

• chr10-16969176-A-G
• rs1398431
• NM_001081.4:c.4695+13308T>C

Variant summary

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

The NM_001081.4(CUBN):​c.4695+13308T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.858 in 152,238 control chromosomes in the GnomAD database, including 56,432 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 0.86 (56432 hom., cov: 33)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.528
• Publications: 5 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.4695+13308T>C		intron_variant	Intron 31 of 66	ENST00000377833.10	NP_001072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.4695+13308T>C		intron_variant	Intron 31 of 66	1	NM_001081.4	ENSP00000367064.4
CUBN	ENST00000438254.1	n.262-3199T>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130562 AN: 152120 Hom.: 56413 Cov.: 33

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.790

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.843

Gnomad FIN AF: 0.922

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.912

Gnomad OTH AF: 0.870

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

GnomAD4 genome AF: 0.858 AC: 130633 AN: 152238 Hom.: 56432 Cov.: 33 AF XY: 0.856 AC XY: 63697 AN XY: 74434

African (AFR) AF: 0.791 AC: 32835 AN: 41512

American (AMR) AF: 0.790 AC: 12079 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 3189 AN: 3472

East Asian (EAS) AF: 0.702 AC: 3629 AN: 5170

South Asian (SAS) AF: 0.844 AC: 4073 AN: 4826

European-Finnish (FIN) AF: 0.922 AC: 9781 AN: 10608

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.912 AC: 62051 AN: 68034

Other (OTH) AF: 0.869 AC: 1837 AN: 2114

Alfa AF: 0.885 Hom.: 166362

Bravo AF: 0.842

Asia WGS AF: 0.792 AC: 2756 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.78
DANN	Benign	0.39
PhyloP100		-0.53
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: rs1398431; hg19: chr10-17011175;