9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC

Variant names:

• chr9-130681605-T-TCGCCGCCGCCGCCGC
• rs752427775
• NM_021619.3:c.1062_1076dupCGCCGCCGCCGCCGC

Variant summary

Our verdict is Likely benign. The variant received -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. 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A359A) has been classified as Likely benign.

• 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, multiple submitters, no conflicts U:2
• 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: Likely_benign. The variant received -1 ACMG points.

• 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.1062_1076dupCGCCGCCGCCGCCGC	p.Ala355_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.1062_1076dupCGCCGCCGCCGCCGC	p.Ala355_Ala359dup	disruptive_inframe_insertion	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+156_906+170dupCGCCGCCGCCGCCGC		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

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

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

African (AFR) AF: 0.0000675 AC: 1 AN: 14820

American (AMR) AF: 0.000785 AC: 1 AN: 1274

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 9 AN: 5224

East Asian (EAS) AF: 0.000505 AC: 2 AN: 3958

South Asian (SAS) AF: 0.000247 AC: 4 AN: 16206

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: 0.000146 AC: 108 AN: 742012

Other (OTH) AF: 0.0000374 AC: 1 AN: 26760

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

African (AFR) AF: 0.000280 AC: 11 AN: 39292

American (AMR) AF: 0.000691 AC: 10 AN: 14472

Ashkenazi Jewish (ASJ) AF: 0.00209 AC: 7 AN: 3350

East Asian (EAS) AF: 0.000427 AC: 2 AN: 4680

South Asian (SAS) AF: 0.00109 AC: 5 AN: 4604

European-Finnish (FIN) AF: 0.000512 AC: 4 AN: 7820

Middle Eastern (MID) AF: 0.00376 AC: 1 AN: 266

European-Non Finnish (NFE) AF: 0.000263 AC: 17 AN: 64610

Other (OTH) AF: 0.00103 AC: 2 AN: 1946

Alfa AF: 0.00 Hom.: 347

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital insensitivity to pain-hypohidrosis syndrome (1)
-	1	-	Hereditary sensory and autonomic neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.091
Mutation Taster		=82/18	polymorphism

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;