rs1209819349

Variant names:

• chr12-21470224-T-G
• rs1209819349
• NM_002907.4:c.1920A>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_002907.4(RECQL):​c.1920A>C​(p.Gly640Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,610,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RECQL NM_002907.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.457
• Publications: 1 publications found

Genes affected

RECQL (HGNC:9948): (RecQ like helicase) The protein encoded by this gene is a member of the RecQ DNA helicase family. DNA helicases are enzymes involved in various types of DNA repair, including mismatch repair, nucleotide excision repair and direct repair. The encoded protein is involved in the processing of Holliday junctions, the suppression of sister chromatid exchanges, telomere maintenance, and is required for genotoxic stress resistance. Defects in this gene have been associated with several types of cancer. [provided by RefSeq, Jan 2017]

PYROXD1 (HGNC:26162): (pyridine nucleotide-disulphide oxidoreductase domain 1) This gene encodes a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins that catalyze the pyridine nucleotide-dependent reduction of thiol residues in other proteins. The encoded protein belongs to the class I pyridine nucleotide-disulphide oxidoreductase family but lacks the C-terminal dimerization domain found in other family members and instead has a C-terminal nitrile reductase domain. It localizes to the nucleus and to striated sarcomeric compartments. Naturally occurring mutations in this gene cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. A pseudogene of this gene has been defined on chromosome 11. [provided by RefSeq, Apr 2017]

PYROXD1 Gene-Disease associations (from GenCC):

• myofibrillar myopathy 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 12-21470224-T-G is Benign according to our data. Variant chr12-21470224-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1568990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.457 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002907.4. 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
	RECQL	NM_002907.4	MANE Select	c.1920A>C	p.Gly640Gly	synonymous	Exon 15 of 15	NP_002898.2
	PYROXD1	NM_024854.5	MANE Select	c.*1470T>G		3_prime_UTR	Exon 12 of 12	NP_079130.2	Q8WU10-1
	RECQL	NM_032941.3		c.1920A>C	p.Gly640Gly	synonymous	Exon 16 of 16	NP_116559.1	P46063

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL	ENST00000444129.7	TSL:2 MANE Select	c.1920A>C	p.Gly640Gly	synonymous	Exon 15 of 15	ENSP00000416739.2	P46063
	RECQL	ENST00000421138.6	TSL:1	c.1920A>C	p.Gly640Gly	synonymous	Exon 16 of 16	ENSP00000395449.2	P46063
	PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.*1470T>G		3_prime_UTR	Exon 12 of 12	ENSP00000240651.9	Q8WU10-1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151772 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248600 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458362 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 725304

African (AFR) AF: 0.00 AC: 0 AN: 33266

American (AMR) AF: 0.00 AC: 0 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 85448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110500

Other (OTH) AF: 0.00 AC: 0 AN: 60228

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151772 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74104

African (AFR) AF: 0.00 AC: 0 AN: 41382

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67872

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.4
DANN	Benign	0.81
PhyloP100		-0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1209819349; hg19: chr12-21623158;