12-6970446-G-A

Variant names:

• chr12-6970446-G-A
• NM_001144831.2:c.98C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001144831.2(PHB2):​c.98C>T​(p.Ala33Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PHB2 NM_001144831.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHB2	NM_001144831.2	c.98C>T	p.Ala33Val	missense_variant	Exon 1 of 10	ENST00000535923.6	NP_001138303.1
PHB2	NM_001267700.1	c.98C>T	p.Ala33Val	missense_variant	Exon 1 of 9		NP_001254629.1
PHB2	XM_047428234.1	c.98C>T	p.Ala33Val	missense_variant	Exon 1 of 6		XP_047284190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHB2	ENST00000535923.6	c.98C>T	p.Ala33Val	missense_variant	Exon 1 of 10	5	NM_001144831.2	ENSP00000441875.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451894 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 722754

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.98C>T (p.A33V) alteration is located in exon 1 (coding exon 1) of the PHB2 gene. This alteration results from a C to T substitution at nucleotide position 98, causing the alanine (A) at amino acid position 33 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T;T;T;T;.;T;T
Eigen	Benign	-0.082
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;.;.;L;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.38	T;T;T;T;T;T;T
Sift4G	Benign	0.31	T;T;T;T;T;.;.
Polyphen		0.0070	.;B;.;.;.;.;.
Vest4		0.67
MutPred		0.44		Gain of catalytic residue at A29 (P = 8e-04);Gain of catalytic residue at A29 (P = 8e-04);Gain of catalytic residue at A29 (P = 8e-04);Gain of catalytic residue at A29 (P = 8e-04);Gain of catalytic residue at A29 (P = 8e-04);Gain of catalytic residue at A29 (P = 8e-04);Gain of catalytic residue at A29 (P = 8e-04);
MVP		0.36
MPC		0.76
ClinPred		0.90	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.29
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-7079609;