NM_001081.4:c.4169-8959A>C

Variant names:

• chr10-16999474-T-G
• rs10508518
• NM_001081.4:c.4169-8959A>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.4169-8959A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 152,174 control chromosomes in the GnomAD database, including 5,824 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 0.26 (5824 hom., cov: 33)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.235
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.4169-8959A>C		intron_variant	Intron 28 of 66	ENST00000377833.10	NP_001072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.4169-8959A>C		intron_variant	Intron 28 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39388 AN: 152056 Hom.: 5820 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.262

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

GnomAD4 genome AF: 0.259 AC: 39411 AN: 152174 Hom.: 5824 Cov.: 33 AF XY: 0.262 AC XY: 19497 AN XY: 74406

African (AFR) AF: 0.106 AC: 4408 AN: 41564

American (AMR) AF: 0.339 AC: 5175 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1123 AN: 3472

East Asian (EAS) AF: 0.416 AC: 2149 AN: 5170

South Asian (SAS) AF: 0.264 AC: 1274 AN: 4828

European-Finnish (FIN) AF: 0.354 AC: 3743 AN: 10572

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20722 AN: 67970

Other (OTH) AF: 0.259 AC: 546 AN: 2110

Alfa AF: 0.277 Hom.: 4823

Bravo AF: 0.256

Asia WGS AF: 0.314 AC: 1091 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.1
DANN	Benign	0.75
PhyloP100		0.23
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: rs10508518; hg19: chr10-17041473;