rs4748353

Variant names:

• chr10-17104668-C-T
• rs4748353
• NM_001081.4:c.1231-63G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-17104668-C-T
• chr10-17104668-C-A
• chr10-17104668-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001081.4(CUBN):​c.1231-63G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.949 in 1,100,476 control chromosomes in the GnomAD database, including 495,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (67429 hom., cov: 27)
  • Exomes 𝑓: 0.95 (428168 hom.)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.399
• Publications: 7 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: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-17104668-C-T is Benign according to our data. Variant chr10-17104668-C-T is described in ClinVar as Benign. ClinVar VariationId is 1259729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001081.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	NM_001081.4	MANE Select	c.1231-63G>A		intron	N/A	NP_001072.2	O60494

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.1231-63G>A		intron	N/A	ENSP00000367064.4	O60494

Frequencies

GnomAD3 genomes AF: 0.951 AC: 141734 AN: 149002 Hom.: 67421 Cov.: 27

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.923

Gnomad ASJ AF: 0.952

Gnomad EAS AF: 0.916

Gnomad SAS AF: 0.944

Gnomad FIN AF: 0.945

Gnomad MID AF: 0.954

Gnomad NFE AF: 0.956

Gnomad OTH AF: 0.951

GnomAD4 exome AF: 0.949 AC: 902469 AN: 951452 Hom.: 428168 AF XY: 0.949 AC XY: 464558 AN XY: 489690

African (AFR) AF: 0.960 AC: 21827 AN: 22728

American (AMR) AF: 0.915 AC: 33823 AN: 36960

Ashkenazi Jewish (ASJ) AF: 0.946 AC: 21062 AN: 22264

East Asian (EAS) AF: 0.928 AC: 30852 AN: 33242

South Asian (SAS) AF: 0.946 AC: 67057 AN: 70902

European-Finnish (FIN) AF: 0.947 AC: 46151 AN: 48732

Middle Eastern (MID) AF: 0.962 AC: 4619 AN: 4800

European-Non Finnish (NFE) AF: 0.951 AC: 636526 AN: 669088

Other (OTH) AF: 0.949 AC: 40552 AN: 42736

GnomAD4 genome AF: 0.951 AC: 141752 AN: 149024 Hom.: 67429 Cov.: 27 AF XY: 0.950 AC XY: 68999 AN XY: 72598

African (AFR) AF: 0.961 AC: 39066 AN: 40664

American (AMR) AF: 0.923 AC: 13671 AN: 14804

Ashkenazi Jewish (ASJ) AF: 0.952 AC: 3302 AN: 3468

East Asian (EAS) AF: 0.916 AC: 4704 AN: 5136

South Asian (SAS) AF: 0.944 AC: 4495 AN: 4762

European-Finnish (FIN) AF: 0.945 AC: 8895 AN: 9408

Middle Eastern (MID) AF: 0.954 AC: 269 AN: 282

European-Non Finnish (NFE) AF: 0.956 AC: 64567 AN: 67560

Other (OTH) AF: 0.950 AC: 1936 AN: 2038

Alfa AF: 0.956 Hom.: 8476

Bravo AF: 0.949

Asia WGS AF: 0.929 AC: 3232 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.5
DANN	Benign	0.31
PhyloP100		-0.40
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: rs4748353; hg19: chr10-17146667;