NM_018035.3:c.706T>G

Variant names:

• chr19-41432299-A-C
• NM_018035.3:c.706T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018035.3(DMAC2):​c.706T>G​(p.Trp236Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DMAC2 NM_018035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• Publications: 0 publications found

Genes affected

DMAC2 (HGNC:25496): (distal membrane arm assembly component 2) Involved in mitochondrial respiratory chain complex I assembly. Colocalizes with mitochondrial respiratory chain complex I. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018035.3. 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
	DMAC2	NM_018035.3	MANE Select	c.706T>G	p.Trp236Gly	missense	Exon 6 of 6	NP_060505.2	Q9NW81-1
	DMAC2	NM_001167867.2		c.724T>G	p.Trp242Gly	missense	Exon 6 of 6	NP_001161339.1	Q9NW81-4
	DMAC2	NM_001320840.2		c.643T>G	p.Trp215Gly	missense	Exon 5 of 5	NP_001307769.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMAC2	ENST00000221943.14	TSL:2 MANE Select	c.706T>G	p.Trp236Gly	missense	Exon 6 of 6	ENSP00000221943.8	Q9NW81-1
	DMAC2	ENST00000438807.7	TSL:1	c.462T>G	p.Thr154Thr	synonymous	Exon 4 of 4	ENSP00000397413.3	Q9NW81-2
	DMAC2	ENST00000417807.7	TSL:2	c.724T>G	p.Trp242Gly	missense	Exon 6 of 6	ENSP00000403910.2	Q9NW81-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.80
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-1.0	T
PhyloP100		3.2
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.022	D
Polyphen		0.82	P
Vest4		0.46
MutPred		0.65		Gain of disorder (P = 9e-04)
MVP		0.52
MPC		0.89
ClinPred		0.94	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.54
Mutation Taster		=90/10	polymorphism

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

hg19: chr19-41938204;