1-235448220-CAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAA

Variant names:

• chr1-235448220-C-CAA
• rs59405398
• NM_152490.5:c.*1984_*1985dupTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_152490.5(B3GALNT2):​c.*1984_*1985dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 520,352 control chromosomes in the GnomAD database, including 120 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.047 (119 hom., cov: 24)
  • Exomes 𝑓: 0.018 (1 hom.)
• Consequence: B3GALNT2 NM_152490.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.40
• Publications: 0 publications found

Genes affected

B3GALNT2 (HGNC:28596): (beta-1,3-N-acetylgalactosaminyltransferase 2) This gene encodes a member of the glycosyltransferase 31 family. The encoded protein synthesizes GalNAc:beta-1,3GlcNAc, a novel carbohydrate structure, on N- and O-glycans. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Mar 2013]

TBCE (HGNC:11582): (tubulin folding cofactor E) Cofactor E is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

TBCE Gene-Disease associations (from GenCC):

• hypoparathyroidism-retardation-dysmorphism syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P
• early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• encephalopathy, progressive, with amyotrophy and optic atrophy

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, ClinGen, G2P, Ambry Genetics
• autosomal recessive Kenny-Caffey syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ENSG00000285053 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-235448220-C-CAA is Benign according to our data. Variant chr1-235448220-C-CAA is described in ClinVar as Benign. ClinVar VariationId is 1250633.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0877 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152490.5. 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
	B3GALNT2	NM_152490.5	MANE Select	c.*1984_*1985dupTT		3_prime_UTR	Exon 12 of 12	NP_689703.1	Q8NCR0-1
	TBCE	NM_003193.5	MANE Select	c.1400-110_1400-109dupAA		intron	N/A	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.1553-110_1553-109dupAA		intron	N/A	NP_001274730.1	Q15813-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B3GALNT2	ENST00000366600.8	TSL:1 MANE Select	c.*1984_*1985dupTT		3_prime_UTR	Exon 12 of 12	ENSP00000355559.3	Q8NCR0-1
	TBCE	ENST00000642610.2	MANE Select	c.1400-110_1400-109dupAA		intron	N/A	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.1400-110_1400-109dupAA		intron	N/A	ENSP00000494775.1

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 3076 AN: 65468 Hom.: 118 Cov.: 24

Gnomad AFR AF: 0.0909

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.0777

Gnomad EAS AF: 0.000602

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00362

Gnomad MID AF: 0.0725

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.0385

GnomAD4 exome AF: 0.0178 AC: 8117 AN: 454866 Hom.: 1 AF XY: 0.0176 AC XY: 4331 AN XY: 246624

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

African (AFR) AF: 0.0611 AC: 661 AN: 10816

American (AMR) AF: 0.0137 AC: 326 AN: 23846

Ashkenazi Jewish (ASJ) AF: 0.0273 AC: 409 AN: 14978

East Asian (EAS) AF: 0.00921 AC: 256 AN: 27786

South Asian (SAS) AF: 0.0128 AC: 656 AN: 51158

European-Finnish (FIN) AF: 0.00885 AC: 257 AN: 29050

Middle Eastern (MID) AF: 0.0151 AC: 44 AN: 2908

European-Non Finnish (NFE) AF: 0.0184 AC: 4972 AN: 269950

Other (OTH) AF: 0.0220 AC: 536 AN: 24374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0470 AC: 3080 AN: 65486 Hom.: 119 Cov.: 24 AF XY: 0.0463 AC XY: 1415 AN XY: 30540

African (AFR) AF: 0.0911 AC: 1902 AN: 20876

American (AMR) AF: 0.0259 AC: 147 AN: 5674

Ashkenazi Jewish (ASJ) AF: 0.0777 AC: 127 AN: 1634

East Asian (EAS) AF: 0.000602 AC: 1 AN: 1660

South Asian (SAS) AF: 0.0165 AC: 26 AN: 1580

European-Finnish (FIN) AF: 0.00362 AC: 9 AN: 2484

Middle Eastern (MID) AF: 0.0794 AC: 10 AN: 126

European-Non Finnish (NFE) AF: 0.0273 AC: 825 AN: 30224

Other (OTH) AF: 0.0380 AC: 33 AN: 868

Alfa AF: 0.00192 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs59405398; hg19: chr1-235611535;