NM_001081.4:c.1911C>T

Variant names:

• chr10-17088200-G-A
• rs41289311
• NM_001081.4:c.1911C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001081.4(CUBN):​c.1911C>T​(p.Leu637Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 1,612,820 control chromosomes in the GnomAD database, including 2,835 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (204 hom., cov: 31)
  • Exomes 𝑓: 0.044 (2631 hom.)
• Consequence: CUBN NM_001081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.343
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 10-17088200-G-A is Benign according to our data. Variant chr10-17088200-G-A is described in ClinVar as Benign. ClinVar VariationId is 299519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.343 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

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.1911C>T	p.Leu637Leu	synonymous	Exon 15 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.1911C>T	p.Leu637Leu	synonymous	Exon 15 of 67	ENSP00000367064.4	O60494

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5371 AN: 151922 Hom.: 205 Cov.: 31

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.0892

Gnomad EAS AF: 0.0220

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.0521

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0388

GnomAD2 exomes AF: 0.0536 AC: 13480 AN: 251284 AF XY: 0.0627

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.0857

Gnomad EAS exome AF: 0.0205

Gnomad FIN exome AF: 0.0478

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.0501

GnomAD4 exome AF: 0.0435 AC: 63583 AN: 1460780 Hom.: 2631 Cov.: 31 AF XY: 0.0484 AC XY: 35154 AN XY: 726762

African (AFR) AF: 0.0116 AC: 387 AN: 33478

American (AMR) AF: 0.0232 AC: 1039 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0876 AC: 2289 AN: 26118

East Asian (EAS) AF: 0.0195 AC: 775 AN: 39686

South Asian (SAS) AF: 0.188 AC: 16227 AN: 86170

European-Finnish (FIN) AF: 0.0470 AC: 2508 AN: 53416

Middle Eastern (MID) AF: 0.0876 AC: 505 AN: 5766

European-Non Finnish (NFE) AF: 0.0332 AC: 36854 AN: 1111094

Other (OTH) AF: 0.0497 AC: 2999 AN: 60328

GnomAD4 genome AF: 0.0353 AC: 5367 AN: 152040 Hom.: 204 Cov.: 31 AF XY: 0.0389 AC XY: 2894 AN XY: 74306

African (AFR) AF: 0.0107 AC: 443 AN: 41480

American (AMR) AF: 0.0272 AC: 415 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0892 AC: 309 AN: 3464

East Asian (EAS) AF: 0.0221 AC: 114 AN: 5162

South Asian (SAS) AF: 0.203 AC: 976 AN: 4798

European-Finnish (FIN) AF: 0.0521 AC: 550 AN: 10562

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0347 AC: 2360 AN: 68002

Other (OTH) AF: 0.0388 AC: 82 AN: 2112

Alfa AF: 0.0327 Hom.: 172

Bravo AF: 0.0287

Asia WGS AF: 0.0760 AC: 264 AN: 3478

EpiCase AF: 0.0451

EpiControl AF: 0.0446

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Imerslund-Grasbeck syndrome type 1 (2)
-	-	2	not provided (2)
-	-	1	Imerslund-Grasbeck syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.1
DANN	Benign	0.62
PhyloP100		-0.34
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41289311; hg19: chr10-17130199; COSMIC: COSV64708533;