rs386833773

chr10-17071565-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001081.4(CUBN):c.2486C>T(p.Ser829Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S829S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CUBN NM_001081.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.54

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 10-17071565-G-A is Pathogenic according to our data. Variant chr10-17071565-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56326.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-17071565-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.2486C>T	p.Ser829Leu	missense_variant	19/67	ENST00000377833.10
CUBN	XM_011519708.3	c.2486C>T	p.Ser829Leu	missense_variant	19/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.2486C>T	p.Ser829Leu	missense_variant	19/67	1	NM_001081.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461552 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Imerslund-Grasbeck syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.026	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.92		Loss of disorder (P = 0.1771);
MVP		0.84
MPC		0.41
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.38
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386833773; hg19: chr10-17113564;