12-6970229-T-C

Position:

• chr12-6970229-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001144831.2(PHB2):​c.179A>G​(p.Gln60Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHB2 NM_001144831.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60

Genes affected

PHB2 (HGNC:30306): (prohibitin 2) Enables several functions, including protein C-terminus binding activity; protein N-terminus binding activity; and protein dimerization activity. Involved in several processes, including defense response to virus; positive regulation of cell cycle phase transition; and regulation of transcription, DNA-templated. Located in several cellular components, including cell surface; mitochondrial membrane; and nuclear matrix. Part of mitochondrial prohibitin complex. [provided by Alliance of Genome Resources, Apr 2022]

PHB2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2881678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHB2	NM_001144831.2	c.179A>G	p.Gln60Arg	missense_variant	2/10	ENST00000535923.6	NP_001138303.1
PHB2	NM_001267700.1	c.179A>G	p.Gln60Arg	missense_variant	2/9		NP_001254629.1
PHB2	XM_047428234.1	c.179A>G	p.Gln60Arg	missense_variant	2/6		XP_047284190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHB2	ENST00000535923.6	c.179A>G	p.Gln60Arg	missense_variant	2/10	5	NM_001144831.2	ENSP00000441875.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249134 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135164

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2021

The c.179A>G (p.Q60R) alteration is located in exon 2 (coding exon 2) of the PHB2 gene. This alteration results from a A to G substitution at nucleotide position 179, causing the glutamine (Q) at amino acid position 60 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	T;T;T;T;.;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.74	T;T;T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.93	.;L;.;.;L;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.46	N;N;N;N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.12	T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;.;.
Polyphen		0.0010	.;B;.;.;.;.;.
Vest4		0.45
MutPred		0.46		Gain of catalytic residue at I55 (P = 0.0012);Gain of catalytic residue at I55 (P = 0.0012);Gain of catalytic residue at I55 (P = 0.0012);Gain of catalytic residue at I55 (P = 0.0012);Gain of catalytic residue at I55 (P = 0.0012);Gain of catalytic residue at I55 (P = 0.0012);Gain of catalytic residue at I55 (P = 0.0012);
MVP		0.92
MPC		0.79
ClinPred		0.34	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.19
gMVP		0.54

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: rs782789706; hg19: chr12-7079392;