NM_001081.4:c.10764+512A>C

Variant names:

• chr10-16828293-T-G
• rs7918972
• NM_001081.4:c.10764+512A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001081.4(CUBN):​c.10764+512A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,136 control chromosomes in the GnomAD database, including 2,102 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2102 hom., cov: 32)
• Consequence: CUBN NM_001081.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.77
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4	c.10764+512A>C		intron_variant	Intron 66 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3	c.6750+512A>C		intron_variant	Intron 40 of 40		XP_011518011.1
CUBN	XM_011519710.3	c.6726+512A>C		intron_variant	Intron 40 of 40		XP_011518012.1
CUBN	XM_011519711.4	c.6606+512A>C		intron_variant	Intron 39 of 39		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10	c.10764+512A>C		intron_variant	Intron 66 of 66	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22985 AN: 152018 Hom.: 2096 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.133

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.151 AC: 23007 AN: 152136 Hom.: 2102 Cov.: 32 AF XY: 0.160 AC XY: 11873 AN XY: 74366

African (AFR) AF: 0.143 AC: 5951 AN: 41516

American (AMR) AF: 0.146 AC: 2229 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3472

East Asian (EAS) AF: 0.431 AC: 2220 AN: 5154

South Asian (SAS) AF: 0.219 AC: 1056 AN: 4818

European-Finnish (FIN) AF: 0.228 AC: 2406 AN: 10574

Middle Eastern (MID) AF: 0.113 AC: 33 AN: 292

European-Non Finnish (NFE) AF: 0.120 AC: 8147 AN: 68006

Other (OTH) AF: 0.140 AC: 296 AN: 2112

Alfa AF: 0.106 Hom.: 459

Bravo AF: 0.144

Asia WGS AF: 0.333 AC: 1154 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.49
DANN	Benign	0.38
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs7918972; hg19: chr10-16870292;