2-26192329-G-T

Position:

• chr2-26192329-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000182.5(HADHA):​c.1981C>A​(p.Leu661Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,435,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L661L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HADHA NM_000182.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.703

Genes affected

HADHA (HGNC:4801): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha) This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. Mutations in this gene result in trifunctional protein deficiency or LCHAD deficiency. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. [provided by RefSeq, Jul 2008]

GAREM2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055333227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HADHA	NM_000182.5	c.1981C>A	p.Leu661Met	missense_variant	18/20	ENST00000380649.8
GAREM2	XM_011532567.4	c.1683+5014G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADHA	ENST00000380649.8	c.1981C>A	p.Leu661Met	missense_variant	18/20	1	NM_000182.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1435426 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 715884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	2.0
DANN	Benign	0.84
DEOGEN2	Benign	0.31	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.16	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.055	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L;.;.
MutationTaster	Benign	0.68	D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.84	N;.;.
REVEL	Benign	0.20
Sift	Benign	0.21	T;.;.
Sift4G	Benign	0.17	T;.;.
Polyphen		0.011	B;.;.
Vest4		0.22
MutPred		0.33		Loss of methylation at K660 (P = 0.052);Loss of methylation at K660 (P = 0.052);.;
MVP		0.49
MPC		0.21
ClinPred		0.10	T
GERP RS		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.23
gMVP		0.42

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: rs142348718; hg19: chr2-26415198;