NM_001081.4:c.*420C>T

Variant names:

• chr10-16824555-G-A
• rs182278265
• NM_001081.4:c.*420C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001081.4(CUBN):​c.*420C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 162,264 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: CUBN NM_001081.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.19
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).
• BP6: Variant 10-16824555-G-A is Benign according to our data. Variant chr10-16824555-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 299336.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00316 (475/150102) while in subpopulation AFR AF = 0.0108 (438/40738). AF 95% confidence interval is 0.00992. There are 2 homozygotes in GnomAd4. There are 247 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.*420C>T		3_prime_UTR_variant	Exon 67 of 67	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3	c.*420C>T		3_prime_UTR_variant	Exon 41 of 41		XP_011518011.1
CUBN	XM_011519710.3	c.*420C>T		3_prime_UTR_variant	Exon 41 of 41		XP_011518012.1
CUBN	XM_011519711.4	c.*420C>T		3_prime_UTR_variant	Exon 40 of 40		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.*420C>T		3_prime_UTR_variant	Exon 67 of 67	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 473 AN: 149982 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00119

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000424

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00293

GnomAD4 exome AF: 0.000329 AC: 4 AN: 12162 Hom.: 0 Cov.: 0 AF XY: 0.000157 AC XY: 1 AN XY: 6370

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00690 AC: 2 AN: 290

American (AMR) AF: 0.00 AC: 0 AN: 1738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 174

East Asian (EAS) AF: 0.00 AC: 0 AN: 786

South Asian (SAS) AF: 0.000631 AC: 1 AN: 1586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 24

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 6670

Other (OTH) AF: 0.00154 AC: 1 AN: 648

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.013250), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00316 AC: 475 AN: 150102 Hom.: 2 Cov.: 32 AF XY: 0.00337 AC XY: 247 AN XY: 73254

African (AFR) AF: 0.0108 AC: 438 AN: 40738

American (AMR) AF: 0.00119 AC: 18 AN: 15094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5042

South Asian (SAS) AF: 0.000424 AC: 2 AN: 4716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000163 AC: 11 AN: 67558

Other (OTH) AF: 0.00290 AC: 6 AN: 2072

Alfa AF: 0.000417 Hom.: 0

Bravo AF: 0.00331

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.22
DANN	Benign	0.45
PhyloP100		-3.2

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: rs182278265; hg19: chr10-16866554;