9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC

Position:

• chr9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_021619.3(PRDM12):​c.1068_1076dupCGCCGCCGC​(p.Ala357_Ala359dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (7 hom., cov: 0)
  • Exomes 𝑓: 0.0025 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM12 NM_021619.3 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B: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 Benign. Variant got -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_021619.3
• BP6: Variant 9-130681605-T-TCGCCGCCGC is Benign according to our data. Variant chr9-130681605-T-TCGCCGCCGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475810.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00451 (640/141910) while in subpopulation AMR AF= 0.00629 (91/14472). AF 95% confidence interval is 0.00533. There are 7 homozygotes in gnomad4. There are 333 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM12	NM_021619.3	c.1068_1076dupCGCCGCCGC	p.Ala357_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.1068_1076dupCGCCGCCGC	p.Ala357_Ala359dup	disruptive_inframe_insertion	5/5	1	NM_021619.3	ENSP00000253008.2
PRDM12	ENST00000676323.1	c.906+162_906+170dupCGCCGCCGC		intron_variant				ENSP00000502471.1

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 640 AN: 141870 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.00597

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.00149

Gnomad EAS AF: 0.00490

Gnomad SAS AF: 0.00520

Gnomad FIN AF: 0.00946

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.00207

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00254 AC: 2068 AN: 813110 Hom.: 2 Cov.: 6 AF XY: 0.00265 AC XY: 1000 AN XY: 377138

Gnomad4 AFR exome AF: 0.00722

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00455

Gnomad4 SAS exome AF: 0.00593

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.00238

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00451 AC: 640 AN: 141910 Hom.: 7 Cov.: 0 AF XY: 0.00484 AC XY: 333 AN XY: 68752

Gnomad4 AFR AF: 0.00596

Gnomad4 AMR AF: 0.00629

Gnomad4 ASJ AF: 0.00149

Gnomad4 EAS AF: 0.00491

Gnomad4 SAS AF: 0.00522

Gnomad4 FIN AF: 0.00946

Gnomad4 NFE AF: 0.00282

Gnomad4 OTH AF: 0.00206

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital insensitivity to pain-hypohidrosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 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 or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with PRDM12-related conditions. ClinVar contains an entry for this variant (Variation ID: 475810). 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.1068_1076dup, results in the insertion of 3 amino acid(s) to the PRDM12 protein (p.Ala357_Ala359dup), but otherwise preserves the integrity of the reading frame. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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;