18-12329537-C-G

Variant names:

• chr18-12329537-C-G
• rs1129115
• NM_006796.3:c.*28G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006796.3(AFG3L2):​c.*28G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,603,688 control chromosomes in the GnomAD database, including 47,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6663 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40662 hom.)
• Consequence: AFG3L2 NM_006796.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.111
• Publications: 14 publications found

Genes affected

AFG3L2 (HGNC:315): (AFG3 like matrix AAA peptidase subunit 2) This gene encodes a protein localized in mitochondria and closely related to paraplegin. The paraplegin gene is responsible for an autosomal recessive form of hereditary spastic paraplegia. This gene is a candidate gene for other hereditary spastic paraplegias or neurodegenerative disorders. [provided by RefSeq, Jul 2008]

TUBB6 (HGNC:20776): (tubulin beta 6 class V) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

TUBB6 Gene-Disease associations (from GenCC):

• facial palsy, congenital, with ptosis and velopharyngeal dysfunction

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-12329537-C-G is Benign according to our data. Variant chr18-12329537-C-G is described in ClinVar as Benign. ClinVar VariationId is 326101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006796.3. 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
	AFG3L2	NM_006796.3	MANE Select	c.*28G>C		3_prime_UTR	Exon 17 of 17	NP_006787.2	Q9Y4W6
	TUBB6	NM_001303525.2		c.*354C>G		3_prime_UTR	Exon 4 of 4	NP_001290454.1	K7EJ64

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG3L2	ENST00000269143.8	TSL:1 MANE Select	c.*28G>C		3_prime_UTR	Exon 17 of 17	ENSP00000269143.2	Q9Y4W6
	TUBB6	ENST00000591909.5	TSL:1	c.*354C>G		3_prime_UTR	Exon 4 of 4	ENSP00000465040.1	K7EJ64
	AFG3L2	ENST00000889396.1		c.*28G>C		3_prime_UTR	Exon 18 of 18	ENSP00000559455.1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42779 AN: 151966 Hom.: 6644 Cov.: 32

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.291

GnomAD2 exomes AF: 0.267 AC: 67122 AN: 251116 AF XY: 0.258

Gnomad AFR exome AF: 0.399

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.381

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.229 AC: 332489 AN: 1451604 Hom.: 40662 Cov.: 29 AF XY: 0.228 AC XY: 165045 AN XY: 722768

African (AFR) AF: 0.394 AC: 13082 AN: 33164

American (AMR) AF: 0.406 AC: 18154 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 6465 AN: 26080

East Asian (EAS) AF: 0.392 AC: 15546 AN: 39660

South Asian (SAS) AF: 0.217 AC: 18644 AN: 86046

European-Finnish (FIN) AF: 0.169 AC: 9014 AN: 53372

Middle Eastern (MID) AF: 0.247 AC: 1199 AN: 4860

European-Non Finnish (NFE) AF: 0.214 AC: 235810 AN: 1103748

Other (OTH) AF: 0.243 AC: 14575 AN: 59966

GnomAD4 genome AF: 0.282 AC: 42839 AN: 152084 Hom.: 6663 Cov.: 32 AF XY: 0.280 AC XY: 20824 AN XY: 74326

African (AFR) AF: 0.393 AC: 16289 AN: 41448

American (AMR) AF: 0.354 AC: 5410 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 874 AN: 3464

East Asian (EAS) AF: 0.371 AC: 1921 AN: 5176

South Asian (SAS) AF: 0.220 AC: 1064 AN: 4826

European-Finnish (FIN) AF: 0.155 AC: 1643 AN: 10588

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14739 AN: 67990

Other (OTH) AF: 0.289 AC: 610 AN: 2114

Alfa AF: 0.246 Hom.: 947

Bravo AF: 0.304

Asia WGS AF: 0.314 AC: 1097 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Spinocerebellar ataxia type 28 (2)
-	-	1	Optic atrophy 12 (1)
-	-	1	Spastic ataxia 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.53
PhyloP100		-0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1129115; hg19: chr18-12329536; COSMIC: COSV52317679; COSMIC: COSV52317679;