rs146995189

Variant names:

• chr10-16928286-G-C
• rs146995189
• NM_001081.4:c.6142C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-16928286-G-C
• chr10-16928286-G-A
• chr10-16928286-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001081.4(CUBN):​c.6142C>G​(p.Gln2048Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 5.82
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047104955).
• BP6: Variant 10-16928286-G-C is Benign according to our data. Variant chr10-16928286-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 532209.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00131 (199/152156) while in subpopulation AFR AF = 0.00463 (192/41480). AF 95% confidence interval is 0.00409. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.6142C>G	p.Gln2048Glu	missense	Exon 41 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.6142C>G	p.Gln2048Glu	missense	Exon 41 of 67	ENSP00000367064.4	O60494

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152040 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00462

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000343 AC: 86 AN: 250838 AF XY: 0.000280

Gnomad AFR exome AF: 0.00505

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 217 AN: 1461656 Hom.: 0 Cov.: 32 AF XY: 0.000127 AC XY: 92 AN XY: 727124

African (AFR) AF: 0.00586 AC: 196 AN: 33466

American (AMR) AF: 0.0000671 AC: 3 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111874

Other (OTH) AF: 0.000215 AC: 13 AN: 60364

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.00128 AC XY: 95 AN XY: 74386

African (AFR) AF: 0.00463 AC: 192 AN: 41480

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00143 AC: 3 AN: 2104

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.00151

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CUBN-related disorder (1)
-	-	1	Imerslund-Grasbeck syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.0066
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.21	N
PhyloP100		5.8
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.14
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Polyphen		0.33	B
Vest4		0.18
MVP		0.50
MPC		0.087
ClinPred		0.047	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.54
Mutation Taster		=90/10	polymorphism

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: rs146995189; hg19: chr10-16970285;