chr15-45402610-G-A

Variant names:

• chr15-45402610-G-A
• rs1171334745
• NM_024063.3:c.181G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024063.3(AFG2B):​c.181G>A​(p.Ala61Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,423,130 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A61P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AFG2B NM_024063.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.81
• Publications: 0 publications found

Genes affected

AFG2B (HGNC:28762): (AFG2 AAA ATPase homolog B) Predicted to enable ATP binding activity. Located in cytoplasm and spindle. [provided by Alliance of Genome Resources, Apr 2022]

AFG2B Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive 119

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
• neurodevelopmental disorder with hearing loss and spasticity

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024063.3. 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
	AFG2B	NM_024063.3	MANE Select	c.181G>A	p.Ala61Thr	missense	Exon 1 of 8	NP_076968.2	Q9BVQ7-1
	AFG2B	NM_001323640.2		c.181G>A	p.Ala61Thr	missense	Exon 1 of 5	NP_001310569.1	Q9BVQ7-2
	AFG2B	NR_027635.2		n.275G>A		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2B	ENST00000305560.11	TSL:1 MANE Select	c.181G>A	p.Ala61Thr	missense	Exon 1 of 8	ENSP00000305494.6	Q9BVQ7-1
	AFG2B	ENST00000907461.1		c.181G>A	p.Ala61Thr	missense	Exon 1 of 8	ENSP00000577520.1
	AFG2B	ENST00000960280.1		c.181G>A	p.Ala61Thr	missense	Exon 1 of 8	ENSP00000630339.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000563 AC: 1 AN: 177540 AF XY: 0.0000102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000135

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1423130 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 705586

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32356

American (AMR) AF: 0.00 AC: 0 AN: 39814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.00 AC: 0 AN: 37138

South Asian (SAS) AF: 0.00 AC: 0 AN: 82490

European-Finnish (FIN) AF: 0.0000221 AC: 1 AN: 45208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096050

Other (OTH) AF: 0.00 AC: 0 AN: 58980

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.017	D
Sift4G	Benign	0.072	T
Polyphen		0.89	P
Vest4		0.33
MutPred		0.40		Gain of phosphorylation at A61 (P = 0.1039)
MVP		0.95
MPC		1.4
ClinPred		0.97	D
GERP RS		4.9
PromoterAI		-0.083	Neutral
Varity_R		0.28
gMVP		0.72

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: rs1171334745; hg19: chr15-45694808;