rs1801228

Variant names:

• chr10-17046007-T-C
• rs1801228
• NM_001081.4:c.3417A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-17046007-T-C
• chr10-17046007-T-A
• chr10-17046007-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001081.4(CUBN):​c.3417A>G​(p.Leu1139Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 1,613,820 control chromosomes in the GnomAD database, including 3,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (227 hom., cov: 31)
  • Exomes 𝑓: 0.045 (2990 hom.)
• Consequence: CUBN NM_001081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.62
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-17046007-T-C is Benign according to our data. Variant chr10-17046007-T-C is described in ClinVar as Benign. ClinVar VariationId is 299490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.213 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.3417A>G	p.Leu1139Leu	synonymous	Exon 24 of 67	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.3417A>G	p.Leu1139Leu	synonymous	Exon 24 of 67	ENSP00000367064.4	O60494

Frequencies

GnomAD3 genomes AF: 0.0356 AC: 5411 AN: 152096 Hom.: 227 Cov.: 31

Gnomad AFR AF: 0.00867

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.0218

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0516

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0396

GnomAD2 exomes AF: 0.0560 AC: 14073 AN: 251336 AF XY: 0.0658

Gnomad AFR exome AF: 0.00978

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0882

Gnomad EAS exome AF: 0.0194

Gnomad FIN exome AF: 0.0478

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.0524

GnomAD4 exome AF: 0.0449 AC: 65660 AN: 1461606 Hom.: 2990 Cov.: 31 AF XY: 0.0503 AC XY: 36553 AN XY: 727132

African (AFR) AF: 0.00831 AC: 278 AN: 33472

American (AMR) AF: 0.0239 AC: 1068 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0905 AC: 2365 AN: 26128

East Asian (EAS) AF: 0.0195 AC: 772 AN: 39678

South Asian (SAS) AF: 0.206 AC: 17770 AN: 86252

European-Finnish (FIN) AF: 0.0470 AC: 2508 AN: 53398

Middle Eastern (MID) AF: 0.0892 AC: 514 AN: 5764

European-Non Finnish (NFE) AF: 0.0335 AC: 37253 AN: 1111814

Other (OTH) AF: 0.0519 AC: 3132 AN: 60386

GnomAD4 genome AF: 0.0355 AC: 5404 AN: 152214 Hom.: 227 Cov.: 31 AF XY: 0.0395 AC XY: 2940 AN XY: 74410

African (AFR) AF: 0.00867 AC: 360 AN: 41534

American (AMR) AF: 0.0277 AC: 423 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0916 AC: 318 AN: 3470

East Asian (EAS) AF: 0.0218 AC: 113 AN: 5174

South Asian (SAS) AF: 0.224 AC: 1075 AN: 4806

European-Finnish (FIN) AF: 0.0516 AC: 547 AN: 10600

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0347 AC: 2361 AN: 68018

Other (OTH) AF: 0.0411 AC: 87 AN: 2116

Alfa AF: 0.0346 Hom.: 239

Bravo AF: 0.0282

Asia WGS AF: 0.0940 AC: 325 AN: 3478

EpiCase AF: 0.0453

EpiControl AF: 0.0452

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Imerslund-Grasbeck syndrome type 1 (2)
-	-	2	not provided (2)
-	-	1	Imerslund-Grasbeck syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.49
DANN	Benign	0.80
PhyloP100		-1.6
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: rs1801228; hg19: chr10-17088006; COSMIC: COSV64708530;