rs7070148

Variant names:

• chr10-17122626-A-C
• rs7070148
• NM_001081.4:c.593+169T>G

Your query was ambiguous. Multiple possible variants found:

• chr10-17122626-A-C
• chr10-17122626-A-T

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.593+169T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0882 in 653,454 control chromosomes in the GnomAD database, including 3,576 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (512 hom., cov: 32)
  • Exomes 𝑓: 0.095 (3064 hom.)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.180
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-17122626-A-C is Benign according to our data. Variant chr10-17122626-A-C is described in ClinVar as [Benign]. Clinvar id is 1286315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.593+169T>G		intron_variant	Intron 6 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519708.3	c.593+169T>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+169T>G		intron_variant	Intron 6 of 66	1	NM_001081.4	ENSP00000367064.4
CUBN	ENST00000433666.5	c.255-41T>G		intron_variant	Intron 4 of 4	5		ENSP00000415970.1

Frequencies

GnomAD3 genomes AF: 0.0669 AC: 10177 AN: 152126 Hom.: 513 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0242

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.0907

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0831

Gnomad OTH AF: 0.0684

GnomAD2 exomes AF: 0.0916 AC: 10693 AN: 116756 AF XY: 0.101

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.0423

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0213

Gnomad FIN exome AF: 0.0890

Gnomad NFE exome AF: 0.0878

Gnomad OTH exome AF: 0.0806

GnomAD4 exome AF: 0.0947 AC: 47489 AN: 501210 Hom.: 3064 Cov.: 3 AF XY: 0.103 AC XY: 28172 AN XY: 272392

African (AFR) AF: 0.0203 AC: 264 AN: 13000

American (AMR) AF: 0.0416 AC: 1037 AN: 24938

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 1856 AN: 16668

East Asian (EAS) AF: 0.0207 AC: 608 AN: 29430

South Asian (SAS) AF: 0.223 AC: 12304 AN: 55146

European-Finnish (FIN) AF: 0.0890 AC: 3859 AN: 43380

Middle Eastern (MID) AF: 0.109 AC: 403 AN: 3690

European-Non Finnish (NFE) AF: 0.0862 AC: 24825 AN: 287828

Other (OTH) AF: 0.0860 AC: 2333 AN: 27130

GnomAD4 genome AF: 0.0668 AC: 10174 AN: 152244 Hom.: 512 Cov.: 32 AF XY: 0.0703 AC XY: 5230 AN XY: 74426

African (AFR) AF: 0.0198 AC: 823 AN: 41542

American (AMR) AF: 0.0476 AC: 728 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3468

East Asian (EAS) AF: 0.0243 AC: 126 AN: 5184

South Asian (SAS) AF: 0.239 AC: 1154 AN: 4820

European-Finnish (FIN) AF: 0.0907 AC: 961 AN: 10598

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0831 AC: 5649 AN: 68010

Other (OTH) AF: 0.0705 AC: 149 AN: 2112

Alfa AF: 0.0731 Hom.: 426

Bravo AF: 0.0569

Asia WGS AF: 0.104 AC: 362 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.0
DANN	Benign	0.58
PhyloP100		0.18
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: rs7070148; hg19: chr10-17164625; COSMIC: COSV64701242; COSMIC: COSV64701242;