10-17120315-T-C

Variant names:

• chr10-17120315-T-C
• rs7078169
• NM_001081.4:c.593+2480A>G

Variant summary

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

The NM_001081.4(CUBN):​c.593+2480A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.914 in 152,254 control chromosomes in the GnomAD database, including 63,779 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 0.91 (63779 hom., cov: 33)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.96
• Publications: 0 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 (NFE) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.593+2480A>G		intron_variant	Intron 6 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.593+2480A>G		intron_variant	Intron 6 of 54		XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.593+2480A>G		intron_variant	Intron 6 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.914 AC: 139028 AN: 152136 Hom.: 63740 Cov.: 33

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.938

Gnomad AMR AF: 0.904

Gnomad ASJ AF: 0.952

Gnomad EAS AF: 0.917

Gnomad SAS AF: 0.944

Gnomad FIN AF: 0.945

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.955

Gnomad OTH AF: 0.921

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

GnomAD4 genome AF: 0.914 AC: 139124 AN: 152254 Hom.: 63779 Cov.: 33 AF XY: 0.914 AC XY: 68046 AN XY: 74444

African (AFR) AF: 0.834 AC: 34626 AN: 41518

American (AMR) AF: 0.904 AC: 13841 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.952 AC: 3305 AN: 3472

East Asian (EAS) AF: 0.917 AC: 4751 AN: 5180

South Asian (SAS) AF: 0.944 AC: 4558 AN: 4828

European-Finnish (FIN) AF: 0.945 AC: 10023 AN: 10604

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.955 AC: 64948 AN: 68028

Other (OTH) AF: 0.921 AC: 1947 AN: 2114

Alfa AF: 0.931 Hom.: 8562

Bravo AF: 0.904

Asia WGS AF: 0.924 AC: 3213 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.17
DANN	Benign	0.48
PhyloP100		-2.0
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: rs7078169; hg19: chr10-17162314;