rs200255820

Variant names:

• chr12-6967713-A-C
• NM_001144831.2:c.674T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-6967713-A-C
• chr12-6967713-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001144831.2(PHB2):​c.674T>G​(p.Ile225Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PHB2 NM_001144831.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.07

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]

SCARNA12 (HGNC:32569): (small Cajal body-specific RNA 12) This gene produces a small nuclear RNA that localizes specifically to Cajal bodies, which are conserved subnuclear organelles that are present in the nucleoplasm. This RNA is processed from an intron of the prohibitin 2 host gene. It includes both an H/ACA box and a C/D box, and is thought to guide the pseudouridylation of residue U46 in the U5 small nuclear RNA. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a mutagenesis_site Reduces helicity. Decreases homodimerization and interaction with PHB. Disrupts mitochondrial dynamics. Disrupts mitochondrial-mediated antiviral innate immune response. (size 0) in uniprot entity PHB2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHB2	NM_001144831.2	c.674T>G	p.Ile225Ser	missense_variant	Exon 6 of 10	ENST00000535923.6	NP_001138303.1
PHB2	NM_001267700.1	c.607+179T>G		intron_variant	Intron 5 of 8		NP_001254629.1
PHB2	XM_047428234.1	c.607+179T>G		intron_variant	Intron 5 of 5		XP_047284190.1
SCARNA12	NR_003010.1	n.-107T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHB2	ENST00000535923.6	c.674T>G	p.Ile225Ser	missense_variant	Exon 6 of 10	5	NM_001144831.2	ENSP00000441875.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461632 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727104

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;T;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.2	M;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.3	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;.
Polyphen		0.96	D;.;.;.
Vest4		0.91
MutPred		0.47		Gain of phosphorylation at I225 (P = 0.013);Gain of phosphorylation at I225 (P = 0.013);Gain of phosphorylation at I225 (P = 0.013);.;
MVP		0.69
MPC		2.1
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-7076876;