chr12-32740492-C-T

Variant names:

• chr12-32740492-C-T
• rs148634653
• NM_001278464.2:c.2007C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001278464.2(DNM1L):​c.2007C>T​(p.Leu669Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,613,430 control chromosomes in the GnomAD database, including 517 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (44 hom., cov: 33)
  • Exomes 𝑓: 0.023 (473 hom.)
• Consequence: DNM1L NM_001278464.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.150
• Publications: 5 publications found

Genes affected

DNM1L (HGNC:2973): (dynamin 1 like) This gene encodes a member of the dynamin superfamily of GTPases. The encoded protein mediates mitochondrial and peroxisomal division, and is involved in developmentally regulated apoptosis and programmed necrosis. Dysfunction of this gene is implicated in several neurological disorders, including Alzheimer's disease. Mutations in this gene are associated with the autosomal dominant disorder, encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission (EMPF). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2013]

YARS2 (HGNC:24249): (tyrosyl-tRNA synthetase 2) This gene encodes a mitochondrial protein that catalyzes the attachment of tyrosine to tRNA(Tyr). Mutations in this gene are associated with myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2). [provided by RefSeq, Jan 2011]

YARS2 Gene-Disease associations (from GenCC):

• myopathy, lactic acidosis, and sideroblastic anemia 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• myopathy, lactic acidosis, and sideroblastic anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-32740492-C-T is Benign according to our data. Variant chr12-32740492-C-T is described in ClinVar as Benign. ClinVar VariationId is 137128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0176 (2673/152262) while in subpopulation NFE AF = 0.0283 (1926/68016). AF 95% confidence interval is 0.0273. There are 44 homozygotes in GnomAd4. There are 1277 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278464.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	NM_001278464.2	MANE Plus Clinical	c.2007C>T	p.Leu669Leu	synonymous	Exon 19 of 21	NP_001265393.1
	DNM1L	NM_012062.5	MANE Select	c.1968C>T	p.Leu656Leu	synonymous	Exon 18 of 20	NP_036192.2
	DNM1L	NM_001278465.2		c.1974C>T	p.Leu658Leu	synonymous	Exon 18 of 20	NP_001265394.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	ENST00000553257.6	TSL:2 MANE Plus Clinical	c.2007C>T	p.Leu669Leu	synonymous	Exon 19 of 21	ENSP00000449089.1
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.1968C>T	p.Leu656Leu	synonymous	Exon 18 of 20	ENSP00000450399.1
	DNM1L	ENST00000381000.8	TSL:1	c.1974C>T	p.Leu658Leu	synonymous	Exon 18 of 20	ENSP00000370388.4

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2676 AN: 152144 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.00429

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.00821

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0173

GnomAD2 exomes AF: 0.0180 AC: 4515 AN: 250426 AF XY: 0.0187

Gnomad AFR exome AF: 0.00328

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0350

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0272

Gnomad OTH exome AF: 0.0213

GnomAD4 exome AF: 0.0227 AC: 33120 AN: 1461168 Hom.: 473 Cov.: 30 AF XY: 0.0225 AC XY: 16389 AN XY: 726870

African (AFR) AF: 0.00367 AC: 123 AN: 33472

American (AMR) AF: 0.0133 AC: 593 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0338 AC: 883 AN: 26116

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.00953 AC: 821 AN: 86164

European-Finnish (FIN) AF: 0.0103 AC: 547 AN: 53364

Middle Eastern (MID) AF: 0.0338 AC: 195 AN: 5766

European-Non Finnish (NFE) AF: 0.0258 AC: 28630 AN: 1111560

Other (OTH) AF: 0.0220 AC: 1325 AN: 60352

GnomAD4 genome AF: 0.0176 AC: 2673 AN: 152262 Hom.: 44 Cov.: 33 AF XY: 0.0172 AC XY: 1277 AN XY: 74438

African (AFR) AF: 0.00428 AC: 178 AN: 41566

American (AMR) AF: 0.0163 AC: 249 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4822

European-Finnish (FIN) AF: 0.00821 AC: 87 AN: 10600

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1926 AN: 68016

Other (OTH) AF: 0.0166 AC: 35 AN: 2108

Alfa AF: 0.0230 Hom.: 29

Bravo AF: 0.0175

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0299

EpiControl AF: 0.0315

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 04, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 12, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	6.7
DANN	Benign	0.90
PhyloP100		0.15
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148634653; hg19: chr12-32893426;