rs748620956

Variant names:

• chr11-66866178-TCCGC-T
• rs748620956
• NM_001040716.2:c.1185+5_1185+8delGCGG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BS1_Supporting

The NM_001040716.2(PC):​c.1185+5_1185+8delGCGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,605,122 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: PC NM_001040716.2 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.25
• Publications: 0 publications found

Genes affected

PC (HGNC:8636): (pyruvate carboxylase) This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Mutations in this gene have been associated with pyruvate carboxylase deficiency. Alternatively spliced transcript variants with different 5' UTRs, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

PC Gene-Disease associations (from GenCC):

• pyruvate carboxylase deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• pyruvate carboxylase deficiency, benign type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, infantile form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, severe neonatal type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000263 (40/151892) while in subpopulation NFE AF = 0.000486 (33/67966). AF 95% confidence interval is 0.000355. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040716.2. 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
	PC	NM_001040716.2	MANE Select	c.1185+5_1185+8delGCGG		splice_region intron	N/A	NP_001035806.1	P11498-1
	PC	NM_000920.4		c.1185+5_1185+8delGCGG		splice_region intron	N/A	NP_000911.2	P11498-1
	PC	NM_001439352.1		c.1185+5_1185+8delGCGG		splice_region intron	N/A	NP_001426281.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PC	ENST00000393960.7	TSL:5 MANE Select	c.1185+5_1185+8delGCGG		splice_region intron	N/A	ENSP00000377532.1	P11498-1
	PC	ENST00000393955.6	TSL:1	c.1185+5_1185+8delGCGG		splice_region intron	N/A	ENSP00000377527.2	P11498-1
	PC	ENST00000393958.7	TSL:1	c.1185+5_1185+8delGCGG		splice_region intron	N/A	ENSP00000377530.2	P11498-1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 151892 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000259 AC: 63 AN: 243580 AF XY: 0.000279

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000337

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000343 AC: 499 AN: 1453230 Hom.: 1 AF XY: 0.000349 AC XY: 252 AN XY: 722878

African (AFR) AF: 0.0000898 AC: 3 AN: 33400

American (AMR) AF: 0.000202 AC: 9 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.000430 AC: 37 AN: 86044

European-Finnish (FIN) AF: 0.0000209 AC: 1 AN: 47944

Middle Eastern (MID) AF: 0.000440 AC: 2 AN: 4546

European-Non Finnish (NFE) AF: 0.000392 AC: 435 AN: 1110778

Other (OTH) AF: 0.000200 AC: 12 AN: 60148

GnomAD4 genome AF: 0.000263 AC: 40 AN: 151892 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74184

African (AFR) AF: 0.000121 AC: 5 AN: 41328

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000486 AC: 33 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000208

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	2	-	Pyruvate carboxylase deficiency (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.66		Position offset: -38
DS_DL_spliceai		0.22		Position offset: 9

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

Other links and lift over

dbSNP: rs748620956; hg19: chr11-66633649;