NM_001081.4:c.9454+520G>A

Variant names:

• chr10-16869116-C-T
• rs11591606
• NM_001081.4:c.9454+520G>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.9454+520G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 151,316 control chromosomes in the GnomAD database, including 1,356 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 0.12 (1356 hom., cov: 31)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• 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 = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.9454+520G>A		intron_variant	Intron 59 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3	c.5440+520G>A		intron_variant	Intron 33 of 40		XP_011518011.1
CUBN	XM_011519710.3	c.5416+520G>A		intron_variant	Intron 33 of 40		XP_011518012.1
CUBN	XM_011519711.4	c.5296+520G>A		intron_variant	Intron 32 of 39		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.9454+520G>A		intron_variant	Intron 59 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17544 AN: 151248 Hom.: 1358 Cov.: 31

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.0527

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.131

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

GnomAD4 genome AF: 0.116 AC: 17537 AN: 151316 Hom.: 1356 Cov.: 31 AF XY: 0.112 AC XY: 8270 AN XY: 73878

African (AFR) AF: 0.0308 AC: 1269 AN: 41206

American (AMR) AF: 0.109 AC: 1651 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 516 AN: 3468

East Asian (EAS) AF: 0.00137 AC: 7 AN: 5124

South Asian (SAS) AF: 0.0535 AC: 256 AN: 4788

European-Finnish (FIN) AF: 0.136 AC: 1407 AN: 10344

Middle Eastern (MID) AF: 0.196 AC: 56 AN: 286

European-Non Finnish (NFE) AF: 0.175 AC: 11905 AN: 67904

Other (OTH) AF: 0.130 AC: 271 AN: 2086

Alfa AF: 0.139 Hom.: 2002

Bravo AF: 0.112

Asia WGS AF: 0.0330 AC: 117 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	0.34
DANN	Benign	0.74
PhyloP100		-1.0
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: rs11591606; hg19: chr10-16911115;