15-45402620-G-T

Variant names:

• chr15-45402620-G-T
• rs867575033
• NM_024063.3:c.191G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_024063.3(AFG2B):​c.191G>T​(p.Arg64Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000701 in 1,425,530 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. R64Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AFG2B NM_024063.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.60
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-45402619-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1275865.Status of the report is criteria_provided_single_submitter, 1 stars.

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.191G>T	p.Arg64Leu	missense	Exon 1 of 8	NP_076968.2	Q9BVQ7-1
	AFG2B	NM_001323640.2		c.191G>T	p.Arg64Leu	missense	Exon 1 of 5	NP_001310569.1	Q9BVQ7-2
	AFG2B	NR_027635.2		n.285G>T		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.191G>T	p.Arg64Leu	missense	Exon 1 of 8	ENSP00000305494.6	Q9BVQ7-1
	AFG2B	ENST00000907461.1		c.191G>T	p.Arg64Leu	missense	Exon 1 of 8	ENSP00000577520.1
	AFG2B	ENST00000960280.1		c.191G>T	p.Arg64Leu	missense	Exon 1 of 8	ENSP00000630339.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1425530 Hom.: 0 Cov.: 34 AF XY: 0.00000141 AC XY: 1 AN XY: 707098

⚠️ 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: 32438

American (AMR) AF: 0.00 AC: 0 AN: 40352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25458

East Asian (EAS) AF: 0.00 AC: 0 AN: 37328

South Asian (SAS) AF: 0.00 AC: 0 AN: 82710

European-Finnish (FIN) AF: 0.0000223 AC: 1 AN: 44772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097738

Other (OTH) AF: 0.00 AC: 0 AN: 59068

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.6
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.56
Sift	Benign	0.33	T
Sift4G	Benign	0.31	T
Polyphen		0.51	P
Vest4		0.45
MutPred		0.41		Loss of sheet (P = 0.0181)
MVP		0.83
MPC		1.2
ClinPred		0.98	D
GERP RS		3.7
PromoterAI		0.0022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.86

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: rs867575033; hg19: chr15-45694818;