NM_001040716.2:c.*106G>T

Variant names:

• chr11-66848793-C-A
• rs45505701
• NM_001040716.2:c.*106G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001040716.2(PC):​c.*106G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,445,912 control chromosomes in the GnomAD database, including 538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (78 hom., cov: 33)
  • Exomes 𝑓: 0.021 (460 hom.)
• Consequence: PC NM_001040716.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.107
• Publications: 6 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, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-66848793-C-A is Benign according to our data. Variant chr11-66848793-C-A is described in ClinVar as Benign. ClinVar VariationId is 877797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0196 (2983/152356) while in subpopulation NFE AF = 0.0242 (1645/68020). AF 95% confidence interval is 0.0232. There are 78 homozygotes in GnomAd4. There are 1669 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 AR gene

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.*106G>T		3_prime_UTR	Exon 23 of 23	NP_001035806.1	P11498-1
	PC	NM_000920.4		c.*106G>T		3_prime_UTR	Exon 22 of 22	NP_000911.2	P11498-1
	PC	NM_001439352.1		c.*106G>T		3_prime_UTR	Exon 23 of 23	NP_001426281.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PC	ENST00000393960.7	TSL:5 MANE Select	c.*106G>T		3_prime_UTR	Exon 23 of 23	ENSP00000377532.1	P11498-1
	PC	ENST00000393955.6	TSL:1	c.*106G>T		3_prime_UTR	Exon 21 of 21	ENSP00000377527.2	P11498-1
	PC	ENST00000393958.7	TSL:1	c.*106G>T		3_prime_UTR	Exon 22 of 22	ENSP00000377530.2	P11498-1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2983 AN: 152238 Hom.: 78 Cov.: 33

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0242

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.0208 AC: 26953 AN: 1293556 Hom.: 460 Cov.: 19 AF XY: 0.0206 AC XY: 13375 AN XY: 650542

African (AFR) AF: 0.00231 AC: 70 AN: 30268

American (AMR) AF: 0.00765 AC: 325 AN: 42468

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 264 AN: 24832

East Asian (EAS) AF: 0.00 AC: 0 AN: 38362

South Asian (SAS) AF: 0.00513 AC: 420 AN: 81816

European-Finnish (FIN) AF: 0.0808 AC: 3699 AN: 45778

Middle Eastern (MID) AF: 0.00208 AC: 10 AN: 4814

European-Non Finnish (NFE) AF: 0.0219 AC: 21235 AN: 970484

Other (OTH) AF: 0.0170 AC: 930 AN: 54734

GnomAD4 genome AF: 0.0196 AC: 2983 AN: 152356 Hom.: 78 Cov.: 33 AF XY: 0.0224 AC XY: 1669 AN XY: 74496

African (AFR) AF: 0.00349 AC: 145 AN: 41596

American (AMR) AF: 0.0132 AC: 202 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

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

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4834

European-Finnish (FIN) AF: 0.0843 AC: 895 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0242 AC: 1645 AN: 68020

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0151 Hom.: 10

Bravo AF: 0.0131

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Pyruvate carboxylase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.9
DANN	Benign	0.77
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism

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: rs45505701; hg19: chr11-66616264;