9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC

Variant names:

• chr9-130681605-T-TCGCCGCCGCCGCCGCCGC
• rs752427775
• NM_021619.3:c.1059_1076dupCGCCGCCGCCGCCGCCGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP5_Moderate BP3

The NM_021619.3(PRDM12):​c.1059_1076dupCGCCGCCGCCGCCGCCGC​(p.Ala354_Ala359dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A359A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00025 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM12 NM_021619.3 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0910
• Publications: 1 publications found

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]

PRDM12 Gene-Disease associations (from GenCC):

• congenital insensitivity to pain-hypohidrosis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary sensory and autonomic neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 9-130681605-T-TCGCCGCCGCCGCCGCCGC is Pathogenic according to our data. Variant chr9-130681605-T-TCGCCGCCGCCGCCGCCGC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 848182.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP3: Nonframeshift variant in repetitive region in NM_021619.3

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021619.3. 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
	PRDM12	NM_021619.3	MANE Select	c.1059_1076dupCGCCGCCGCCGCCGCCGC	p.Ala354_Ala359dup	disruptive_inframe_insertion	Exon 5 of 5	NP_067632.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM12	ENST00000253008.3	TSL:1 MANE Select	c.1059_1076dupCGCCGCCGCCGCCGCCGC	p.Ala354_Ala359dup	disruptive_inframe_insertion	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+153_906+170dupCGCCGCCGCCGCCGCCGC		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 43 AN: 141872 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000691

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000256

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000356

Gnomad OTH AF: 0.000518

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000247 AC: 201 AN: 813276 Hom.: 0 Cov.: 6 AF XY: 0.000233 AC XY: 88 AN XY: 377226

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000135 AC: 2 AN: 14820

American (AMR) AF: 0.00 AC: 0 AN: 1274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5224

East Asian (EAS) AF: 0.000253 AC: 1 AN: 3958

South Asian (SAS) AF: 0.00 AC: 0 AN: 16210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1600

European-Non Finnish (NFE) AF: 0.000253 AC: 188 AN: 742004

Other (OTH) AF: 0.000374 AC: 10 AN: 26756

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000303 AC: 43 AN: 141912 Hom.: 0 Cov.: 0 AF XY: 0.000233 AC XY: 16 AN XY: 68754

African (AFR) AF: 0.000407 AC: 16 AN: 39292

American (AMR) AF: 0.0000691 AC: 1 AN: 14472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3350

East Asian (EAS) AF: 0.00 AC: 0 AN: 4680

South Asian (SAS) AF: 0.00 AC: 0 AN: 4604

European-Finnish (FIN) AF: 0.000256 AC: 2 AN: 7820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.000356 AC: 23 AN: 64606

Other (OTH) AF: 0.000514 AC: 1 AN: 1946

Alfa AF: 0.00 Hom.: 347

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital insensitivity to pain-hypohidrosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.091
Mutation Taster		=82/18	disease causing (ClinVar)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs752427775;

hg19: chr9-133556992;