19-41432317-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMAC2	NM_018035.3	c.688G>A	p.Glu230Lys	missense_variant	Exon 6 of 6	ENST00000221943.14	NP_060505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMAC2	ENST00000221943.14	c.688G>A	p.Glu230Lys	missense_variant	Exon 6 of 6	2	NM_018035.3	ENSP00000221943.8

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

GnomAD3 exomes AF: 0.0164 AC: 4127 AN: 251230 Hom.: 41 AF XY: 0.0168 AC XY: 2284 AN XY: 135812

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 SAS exome AF: 0.0104

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

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.0260

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.00939

Gnomad4 FIN exome AF: 0.0337

Gnomad4 NFE exome AF: 0.0220

Gnomad4 OTH exome AF: 0.0179

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

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.0308

Gnomad4 NFE AF: 0.0239

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0198 Hom.: 68

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

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Likely benign and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

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;T;T
MetaRNN	Benign	0.0065	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.85	N;.;N
REVEL	Benign	0.032
Sift	Benign	0.28	T;.;T
Sift4G	Benign	0.38	T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2231943; hg19: chr19-41938222; COSMIC: COSV55727978; COSMIC: COSV55727978;