12-6970429-A-G

Variant names:

• chr12-6970429-A-G
• NM_001144831.2:c.115T>C

Variant summary

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

The NM_001144831.2(PHB2):​c.115T>C​(p.Ser39Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.00

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.115T>C	p.Ser39Pro	missense_variant	Exon 1 of 10	ENST00000535923.6	NP_001138303.1
PHB2	NM_001267700.1	c.115T>C	p.Ser39Pro	missense_variant	Exon 1 of 9		NP_001254629.1
PHB2	XM_047428234.1	c.115T>C	p.Ser39Pro	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.115T>C	p.Ser39Pro	missense_variant	Exon 1 of 10	5	NM_001144831.2	ENSP00000441875.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115T>C (p.S39P) alteration is located in exon 1 (coding exon 1) of the PHB2 gene. This alteration results from a T to C substitution at nucleotide position 115, causing the serine (S) at amino acid position 39 to be replaced by a proline (P). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;D;T;T;.;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.67	T;T;T;T;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	.;M;.;.;M;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.4	D;D;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;.;.
Polyphen		0.88	.;P;.;.;.;.;.
Vest4		0.82
MutPred		0.64		Gain of catalytic residue at V40 (P = 2e-04);Gain of catalytic residue at V40 (P = 2e-04);Gain of catalytic residue at V40 (P = 2e-04);Gain of catalytic residue at V40 (P = 2e-04);Gain of catalytic residue at V40 (P = 2e-04);Gain of catalytic residue at V40 (P = 2e-04);Gain of catalytic residue at V40 (P = 2e-04);
MVP		0.52
MPC		1.9
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.95

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: chr12-7079592;