rs2231943

Variant names:

• chr19-41432317-C-T
• rs2231943
• NM_018035.3:c.688G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_018035.3(DMAC2):​c.688G>A​(p.Glu230Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,614,180 control chromosomes in the GnomAD database, including 391 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (32 hom., cov: 32)
  • Exomes 𝑓: 0.020 (359 hom.)
• Consequence: DMAC2 NM_018035.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.476
• Publications: 13 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065402985).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0153 (2337/152322) while in subpopulation NFE AF = 0.0239 (1627/68034). AF 95% confidence interval is 0.0229. There are 32 homozygotes in GnomAd4. There are 1075 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

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.688G>A	p.Glu230Lys	missense	Exon 6 of 6	NP_060505.2	Q9NW81-1
	DMAC2	NM_001167867.2		c.706G>A	p.Glu236Lys	missense	Exon 6 of 6	NP_001161339.1	Q9NW81-4
	DMAC2	NM_001320840.2		c.625G>A	p.Glu209Lys	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.688G>A	p.Glu230Lys	missense	Exon 6 of 6	ENSP00000221943.8	Q9NW81-1
	DMAC2	ENST00000438807.7	TSL:1	c.444G>A	p.Ala148Ala	synonymous	Exon 4 of 4	ENSP00000397413.3	Q9NW81-2
	DMAC2	ENST00000417807.7	TSL:2	c.706G>A	p.Glu236Lys	missense	Exon 6 of 6	ENSP00000403910.2	Q9NW81-4

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2336 AN: 152204 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0164 AC: 4127 AN: 251230 AF XY: 0.0168

Gnomad AFR exome AF: 0.00339

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.0200 AC: 29194 AN: 1461858 Hom.: 359 Cov.: 31 AF XY: 0.0197 AC XY: 14316 AN XY: 727234

African (AFR) AF: 0.00257 AC: 86 AN: 33478

American (AMR) AF: 0.00378 AC: 169 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 680 AN: 26136

East Asian (EAS) AF: 0.00123 AC: 49 AN: 39700

South Asian (SAS) AF: 0.00939 AC: 810 AN: 86258

European-Finnish (FIN) AF: 0.0337 AC: 1797 AN: 53394

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5768

European-Non Finnish (NFE) AF: 0.0220 AC: 24464 AN: 1112006

Other (OTH) AF: 0.0179 AC: 1079 AN: 60396

GnomAD4 genome AF: 0.0153 AC: 2337 AN: 152322 Hom.: 32 Cov.: 32 AF XY: 0.0144 AC XY: 1075 AN XY: 74470

African (AFR) AF: 0.00327 AC: 136 AN: 41574

American (AMR) AF: 0.00621 AC: 95 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5180

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4830

European-Finnish (FIN) AF: 0.0308 AC: 327 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0239 AC: 1627 AN: 68034

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0195 Hom.: 160

Bravo AF: 0.0121

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0223 AC: 192

ExAC AF: 0.0172 AC: 2092

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0188

EpiControl AF: 0.0191

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.19
DANN	Benign	0.89
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.48
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.032
Sift	Benign	0.28	T
Sift4G	Benign	0.38	T
Polyphen		0.0040	B
Vest4		0.081
MPC		0.19
ClinPred		0.0034	T
GERP RS		-8.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.46
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: rs2231943; hg19: chr19-41938222; COSMIC: COSV55727978; COSMIC: COSV55727978;