12-6966475-T-A

Variant names:

• chr12-6966475-T-A
• rs781932320
• NM_001144831.2:c.815A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001144831.2(PHB2):​c.815A>T​(p.Tyr272Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,458,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. 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. Y272C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PHB2 NM_001144831.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.92
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2261338).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144831.2. 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
	PHB2	NM_001144831.2	MANE Select	c.815A>T	p.Tyr272Phe	missense	Exon 8 of 10	NP_001138303.1	Q99623-1
	PHB2	NM_001267700.1		c.701A>T	p.Tyr234Phe	missense	Exon 7 of 9	NP_001254629.1	Q99623-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHB2	ENST00000535923.6	TSL:5 MANE Select	c.815A>T	p.Tyr272Phe	missense	Exon 8 of 10	ENSP00000441875.1	Q99623-1
	PHB2	ENST00000925249.1		c.815A>T	p.Tyr272Phe	missense	Exon 8 of 9	ENSP00000595308.1
	PHB2	ENST00000440277.6	TSL:5	c.701A>T	p.Tyr234Phe	missense	Exon 7 of 9	ENSP00000412856.1	Q99623-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458588 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 725878

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109044

Other (OTH) AF: 0.0000166 AC: 1 AN: 60258

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.88	T
PhyloP100		3.9
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.034	D
Vest4		0.40
MutPred		0.56		Gain of catalytic residue at S81 (P = 0)
MVP		0.38
ClinPred		0.63	D
GERP RS		2.0
Varity_R		0.26
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs781932320; hg19: chr12-7075638;