rs576450214

chr10-17122872-G-Achr10-17122872-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001081.4(CUBN):c.516C>T(p.Asn172=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,454 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (4 hom.)
• Consequence: CUBN NM_001081.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.192

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 10-17122872-G-A is Benign according to our data. Variant chr10-17122872-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 532208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.192 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000304 (445/1461576) while in subpopulation AMR AF= 0.00939 (420/44722). AF 95% confidence interval is 0.00865. There are 4 homozygotes in gnomad4_exome. There are 171 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUBN	NM_001081.4	c.516C>T	p.Asn172=	synonymous_variant	6/67	ENST00000377833.10
CUBN	XM_011519708.3	c.516C>T	p.Asn172=	synonymous_variant	6/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUBN	ENST00000377833.10	c.516C>T	p.Asn172=	synonymous_variant	6/67	1	NM_001081.4	P1
CUBN	ENST00000433666.5	c.177C>T	p.Asn59=	synonymous_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151766 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00154 AC: 386 AN: 251120 Hom.: 5 AF XY: 0.00105 AC XY: 143 AN XY: 135734

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000304 AC: 445 AN: 1461576 Hom.: 4 Cov.: 33 AF XY: 0.000235 AC XY: 171 AN XY: 727102

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151878 Hom.: 1 Cov.: 32 AF XY: 0.000243 AC XY: 18 AN XY: 74194

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00171

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.000824

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1;C5394384:Proteinuria, chronic benign Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 19, 2021

- -

Imerslund-Grasbeck syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.93
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs576450214; hg19: chr10-17164871; COSMIC: COSV100910587; COSMIC: COSV100910587;