rs568556685

Variant names:

• chr19-15125032-C-A
• rs568556685
• NM_006844.5:c.28G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-15125032-C-A
• chr19-15125032-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006844.5(HACL2):​c.28G>T​(p.Ala10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000192 in 1,563,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A10T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HACL2 NM_006844.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.192
• Publications: 0 publications found

Genes affected

HACL2 (HGNC:6041): (ilvB acetolactate synthase like) The protein encoded by this gene shares similarity with several thiamine pyrophosphate-binding proteins identified in bacteria, yeast, and plants. The highest degree of similarity is found with bacterial acetolactate synthases (AHAS), which are enzymes that catalyze the first step in branched-chain amino acid biosynthesis. [provided by RefSeq, Jul 2008]

ILVBL-AS1 (HGNC:55279): (ILVBL antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054421335).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006844.5. 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
	HACL2	NM_006844.5	MANE Select	c.28G>T	p.Ala10Ser	missense	Exon 2 of 16	NP_006835.2
	ILVBL-AS1	NR_186314.1		n.108+527C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ILVBL	ENST00000263383.8	TSL:1 MANE Select	c.28G>T	p.Ala10Ser	missense	Exon 2 of 16	ENSP00000263383.3	A1L0T0
	ILVBL	ENST00000527093.5	TSL:1	c.28G>T	p.Ala10Ser	missense	Exon 1 of 6	ENSP00000435516.1	E9PJS0
	ILVBL	ENST00000599324.1	TSL:1	n.99G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000122 AC: 2 AN: 164364 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000783

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1411482 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 697472

African (AFR) AF: 0.00 AC: 0 AN: 32250

American (AMR) AF: 0.0000541 AC: 2 AN: 36978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 36932

South Asian (SAS) AF: 0.00 AC: 0 AN: 80314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5372

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086400

Other (OTH) AF: 0.00 AC: 0 AN: 58432

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74490

African (AFR) AF: 0.0000240 AC: 1 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2112

ExAC AF: 0.0000175 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.8
DANN	Benign	0.92
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.19
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.012
Sift	Uncertain	0.022	D
Sift4G	Benign	0.47	T
Polyphen		0.0030	B
Vest4		0.22
MVP		0.26
MPC		0.39
ClinPred		0.076	T
GERP RS		2.7
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.093
gMVP		0.40
Mutation Taster		=96/4	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

dbSNP: rs568556685; hg19: chr19-15235843;