rs2259435

Positions:

• chr6-31529138-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001011700.3(MCCD1):​c.124G>A​(p.Glu42Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,611,260 control chromosomes in the GnomAD database, including 23,750 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2118 hom., cov: 31)
  • Exomes 𝑓: 0.17 (21632 hom.)
• Consequence: MCCD1 NM_001011700.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0410

Genes affected

MCCD1 (HGNC:20668): (mitochondrial coiled-coil domain 1) Predicted to be located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039396584).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCCD1	NM_001011700.3	c.124G>A	p.Glu42Lys	missense_variant	1/2	ENST00000376191.3	NP_001011700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCCD1	ENST00000376191.3	c.124G>A	p.Glu42Lys	missense_variant	1/2	1	NM_001011700.3	ENSP00000365362	P1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24901 AN: 151924 Hom.: 2119 Cov.: 31

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.179 AC: 43982 AN: 246220 Hom.: 4149 AF XY: 0.186 AC XY: 24913 AN XY: 134206

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.164

Gnomad SAS exome AF: 0.254

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.169 AC: 246287 AN: 1459218 Hom.: 21632 Cov.: 67 AF XY: 0.173 AC XY: 125340 AN XY: 725972

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.197

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.260

Gnomad4 FIN exome AF: 0.185

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.164 AC: 24918 AN: 152042 Hom.: 2118 Cov.: 31 AF XY: 0.165 AC XY: 12247 AN XY: 74316

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.163

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.184

Alfa AF: 0.173 Hom.: 4333

Bravo AF: 0.162

TwinsUK AF: 0.173 AC: 640

ALSPAC AF: 0.156 AC: 600

ESP6500AA AF: 0.146 AC: 442

ESP6500EA AF: 0.171 AC: 926

ExAC AF: 0.181 AC: 21307

Asia WGS AF: 0.237 AC: 824 AN: 3478

EpiCase AF: 0.180

EpiControl AF: 0.184

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.0
DANN	Benign	0.90
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.095	N
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.011
Sift	Benign	0.098	T
Sift4G	Benign	0.55	T
Polyphen		0.034	B
Vest4		0.032
MPC		0.20
ClinPred		0.00059	T
GERP RS		-0.64
Varity_R		0.032
gMVP		0.095

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

Publications

LitVar

Other links and lift over

dbSNP: rs2259435; hg19: chr6-31496915; COSMIC: COSV66018513; COSMIC: COSV66018513;