rs78549445

Variant names:

• chr10-17068599-T-G
• rs78549445
• NM_001081.4:c.2791+6A>C

Your query was ambiguous. Multiple possible variants found:

• chr10-17068599-T-G
• chr10-17068599-T-A
• chr10-17068599-T-C

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.2791+6A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,607,084 control chromosomes in the GnomAD database, including 538 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (48 hom., cov: 32)
  • Exomes 𝑓: 0.024 (490 hom.)
• Consequence: CUBN NM_001081.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001364
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.272
• 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: 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=-0.79).
• BP6: Variant 10-17068599-T-G is Benign according to our data. Variant chr10-17068599-T-G is described in ClinVar as Benign. ClinVar VariationId is 299499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.058 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.2791+6A>C		splice_region 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.2791+6A>C		splice_region intron	N/A	ENSP00000367064.4	O60494

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3134 AN: 151898 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.00570

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.0639

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0252

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0244 AC: 6095 AN: 249352 AF XY: 0.0247

Gnomad AFR exome AF: 0.00666

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.0676

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0243

Gnomad OTH exome AF: 0.0255

GnomAD4 exome AF: 0.0241 AC: 35072 AN: 1455070 Hom.: 490 Cov.: 31 AF XY: 0.0242 AC XY: 17497 AN XY: 723874

African (AFR) AF: 0.00379 AC: 126 AN: 33256

American (AMR) AF: 0.0114 AC: 507 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 371 AN: 26080

East Asian (EAS) AF: 0.0511 AC: 2021 AN: 39566

South Asian (SAS) AF: 0.0208 AC: 1776 AN: 85260

European-Finnish (FIN) AF: 0.0326 AC: 1739 AN: 53402

Middle Eastern (MID) AF: 0.00802 AC: 46 AN: 5738

European-Non Finnish (NFE) AF: 0.0242 AC: 26822 AN: 1107048

Other (OTH) AF: 0.0277 AC: 1664 AN: 60154

GnomAD4 genome AF: 0.0206 AC: 3130 AN: 152014 Hom.: 48 Cov.: 32 AF XY: 0.0206 AC XY: 1534 AN XY: 74288

African (AFR) AF: 0.00569 AC: 236 AN: 41504

American (AMR) AF: 0.0190 AC: 289 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.0637 AC: 329 AN: 5166

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4810

European-Finnish (FIN) AF: 0.0327 AC: 345 AN: 10550

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0252 AC: 1710 AN: 67952

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.0189 Hom.: 14

Bravo AF: 0.0190

Asia WGS AF: 0.0670 AC: 234 AN: 3476

EpiCase AF: 0.0243

EpiControl AF: 0.0222

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Imerslund-Grasbeck syndrome (1)
-	-	1	Imerslund-Grasbeck syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.58
PhyloP100		0.27
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.016
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: rs78549445; hg19: chr10-17110598; COSMIC: COSV64716928;