chr18-12358662-C-T

Variant names:

• chr18-12358662-C-T
• rs8091858
• NM_006796.3:c.1026+8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006796.3(AFG3L2):​c.1026+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0248 in 1,613,348 control chromosomes in the GnomAD database, including 588 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (61 hom., cov: 33)
  • Exomes 𝑓: 0.025 (527 hom.)
• Consequence: AFG3L2 NM_006796.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001617
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.171
• Publications: 5 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]

AFG3L2 Gene-Disease associations (from GenCC):

• optic atrophy 12

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• spinocerebellar ataxia type 28

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spastic ataxia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 18-12358662-C-T is Benign according to our data. Variant chr18-12358662-C-T is described in ClinVar as Benign. ClinVar VariationId is 136313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0231 (3523/152324) while in subpopulation NFE AF = 0.0307 (2086/68020). AF 95% confidence interval is 0.0296. There are 61 homozygotes in GnomAd4. There are 1792 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 AR,AD gene

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.1026+8G>A		splice_region intron	N/A	NP_006787.2	Q9Y4W6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG3L2	ENST00000269143.8	TSL:1 MANE Select	c.1026+8G>A		splice_region intron	N/A	ENSP00000269143.2	Q9Y4W6
	AFG3L2	ENST00000889396.1		c.1233+8G>A		splice_region intron	N/A	ENSP00000559455.1
	AFG3L2	ENST00000964861.1		c.1233+8G>A		splice_region intron	N/A	ENSP00000634920.1

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3524 AN: 152206 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0665

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00972

Gnomad FIN AF: 0.0501

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.0259

GnomAD2 exomes AF: 0.0245 AC: 6104 AN: 249578 AF XY: 0.0243

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.0164

Gnomad ASJ exome AF: 0.0618

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0500

Gnomad NFE exome AF: 0.0297

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0250 AC: 36528 AN: 1461024 Hom.: 527 Cov.: 32 AF XY: 0.0249 AC XY: 18096 AN XY: 726770

African (AFR) AF: 0.00353 AC: 118 AN: 33466

American (AMR) AF: 0.0180 AC: 805 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0618 AC: 1613 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00822 AC: 708 AN: 86162

European-Finnish (FIN) AF: 0.0454 AC: 2421 AN: 53354

Middle Eastern (MID) AF: 0.0286 AC: 165 AN: 5760

European-Non Finnish (NFE) AF: 0.0263 AC: 29227 AN: 1111462

Other (OTH) AF: 0.0244 AC: 1471 AN: 60372

GnomAD4 genome AF: 0.0231 AC: 3523 AN: 152324 Hom.: 61 Cov.: 33 AF XY: 0.0241 AC XY: 1792 AN XY: 74490

African (AFR) AF: 0.00491 AC: 204 AN: 41582

American (AMR) AF: 0.0212 AC: 324 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0665 AC: 231 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00973 AC: 47 AN: 4830

European-Finnish (FIN) AF: 0.0501 AC: 532 AN: 10612

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0307 AC: 2086 AN: 68020

Other (OTH) AF: 0.0261 AC: 55 AN: 2110

Alfa AF: 0.0274 Hom.: 118

Bravo AF: 0.0204

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	AFG3L2-related disorder (1)
-	-	1	Spinocerebellar ataxia type 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.5
DANN	Benign	0.63
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.016
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: rs8091858; hg19: chr18-12358661;