9-130681605-T-TCGCCGCCGCCGCCGC

Position:

• chr9-130681605-T-TCGCCGCCGCCGCCGC

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP3

The NM_021619.3(PRDM12):​c.1062_1076dupCGCCGCCGCCGCCGC​(p.Ala355_Ala359dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM12 NM_021619.3 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0910

Genes affected

PRDM12 (HGNC:13997): (PR/SET domain 12) This gene encodes a transcriptional regulator of sensory neuronal specification that plays a critical role in pain perception. The encoded protein contains an N-terminal PRDI-BF1 and RIZ homology (PR) domain, a SET domain, and three C-terminal C2H2 zinc finger DNA-binding domains. Naturally occurring mutations in this gene are associated with congenital insensitivity to pain (CIP), and hereditary sensory and autonomic neuropathies (HSAN's) affecting peripheral sensory and autonomic neurons. Deregulation of this gene is associated with solid cancers and hematological malignancies including chronic myeloid leukaemia. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_021619.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM12	NM_021619.3	c.1062_1076dupCGCCGCCGCCGCCGC	p.Ala355_Ala359dup	disruptive_inframe_insertion	5/5	ENST00000253008.3	NP_067632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM12	ENST00000253008.3	c.1062_1076dupCGCCGCCGCCGCCGC	p.Ala355_Ala359dup	disruptive_inframe_insertion	5/5	1	NM_021619.3	ENSP00000253008.2
PRDM12	ENST00000676323.1	c.906+156_906+170dupCGCCGCCGCCGCCGC		intron_variant				ENSP00000502471.1

Frequencies

GnomAD3 genomes AF: 0.000416 AC: 59 AN: 141876 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000691

Gnomad ASJ AF: 0.00209

Gnomad EAS AF: 0.000426

Gnomad SAS AF: 0.00108

Gnomad FIN AF: 0.000512

Gnomad MID AF: 0.00685

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.000518

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000155 AC: 126 AN: 813284 Hom.: 0 Cov.: 6 AF XY: 0.000162 AC XY: 61 AN XY: 377226

Gnomad4 AFR exome AF: 0.0000675

Gnomad4 AMR exome AF: 0.000785

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.000505

Gnomad4 SAS exome AF: 0.000247

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.0000374

GnomAD4 genome AF: 0.000416 AC: 59 AN: 141916 Hom.: 0 Cov.: 0 AF XY: 0.000393 AC XY: 27 AN XY: 68754

Gnomad4 AFR AF: 0.000280

Gnomad4 AMR AF: 0.000691

Gnomad4 ASJ AF: 0.00209

Gnomad4 EAS AF: 0.000427

Gnomad4 SAS AF: 0.00109

Gnomad4 FIN AF: 0.000512

Gnomad4 NFE AF: 0.000263

Gnomad4 OTH AF: 0.00103

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital insensitivity to pain-hypohidrosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 24, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has not been reported in the literature in individuals with PRDM12-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant, c.1062_1076dup, results in the insertion of 5 amino acid(s) to the PRDM12 protein (p.Ala355_Ala359dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752427775; hg19: chr9-133556992;