12-6966468-T-C

Position:

• chr12-6966468-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001144831.2(PHB2):​c.822A>G​(p.Thr274Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,611,336 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (82 hom.)
• Consequence: PHB2 NM_001144831.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.779

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037773252).
• BP6: Variant 12-6966468-T-C is Benign according to our data. Variant chr12-6966468-T-C is described in ClinVar as [Benign]. Clinvar id is 709112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.779 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00562 (856/152322) while in subpopulation AFR AF= 0.0175 (728/41576). AF 95% confidence interval is 0.0165. There are 10 homozygotes in gnomad4. There are 425 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 856 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHB2	NM_001144831.2	c.822A>G	p.Thr274Thr	synonymous_variant	8/10	ENST00000535923.6	NP_001138303.1
PHB2	NM_001267700.1	c.708A>G	p.Thr236Thr	synonymous_variant	7/9		NP_001254629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHB2	ENST00000535923.6	c.822A>G	p.Thr274Thr	synonymous_variant	8/10	5	NM_001144831.2	ENSP00000441875.1

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 853 AN: 152204 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00152 AC: 379 AN: 249328 Hom.: 4 AF XY: 0.00123 AC XY: 166 AN XY: 135254

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00245

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00180 AC: 2628 AN: 1459014 Hom.: 82 Cov.: 28 AF XY: 0.00171 AC XY: 1238 AN XY: 726044

Gnomad4 AFR exome AF: 0.0178

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0398

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000218

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00562 AC: 856 AN: 152322 Hom.: 10 Cov.: 32 AF XY: 0.00571 AC XY: 425 AN XY: 74494

Gnomad4 AFR AF: 0.0175

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0122

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00258 Hom.: 1

Bravo AF: 0.00587

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0141 AC: 60

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.00182 AC: 220

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 02, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.51
DANN	Benign	0.51
DEOGEN2	Benign	0.0093	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.69	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.063
Sift	Benign	0.072	T
Vest4		0.090
MVP		0.11
ClinPred		0.013	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs34735201; hg19: chr12-7075631;