rs147623570

Variant names:

• chr16-87902425-C-T
• rs147623570
• NM_001739.2:c.555G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PP3_Strong PP5

The NM_001739.2(CA5A):​c.555G>A​(p.Lys185Lys) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000152 in 1,594,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000568852: Published functional studies demonstrate a damaging effect (van Karnebeek et al., 2014" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: CA5A NM_001739.2 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 5.67
• Publications: 9 publications found

Genes affected

CA5A (HGNC:1377): (carbonic anhydrase 5A) Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. CA VA is localized in the mitochondria and expressed primarily in the liver. It may play an important role in ureagenesis and gluconeogenesis. CA5A gene maps to chromosome 16q24.3 and an unprocessed pseudogene has been assigned to 16p12-p11.2. [provided by RefSeq, Jul 2008]

CA5A Gene-Disease associations (from GenCC):

• hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000568852: Published functional studies demonstrate a damaging effect (van Karnebeek et al., 2014; Diez-Fernandez et al., 2016)
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-87902425-C-T is Pathogenic according to our data. Variant chr16-87902425-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127088.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001739.2. 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
	CA5A	NM_001739.2	MANE Select	c.555G>A	p.Lys185Lys	splice_region synonymous	Exon 4 of 7	NP_001730.1	P35218
	CA5A	NM_001367225.1		c.555G>A	p.Lys185Lys	splice_region synonymous	Exon 4 of 7	NP_001354154.1	A0A3B3IRX9
	CA5A	NR_159798.1		n.634G>A		splice_region non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA5A	ENST00000649794.3	MANE Select	c.555G>A	p.Lys185Lys	splice_region synonymous	Exon 4 of 7	ENSP00000498065.2	P35218
	CA5A	ENST00000648177.1		c.436G>A	p.Gly146Arg	missense splice_region	Exon 3 of 5	ENSP00000497626.1	A0A3B3ITA6
	CA5A	ENST00000906212.1		c.690G>A	p.Lys230Lys	splice_region synonymous	Exon 5 of 8	ENSP00000576271.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152102 Hom.: 0 Cov.: 31

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251092 AF XY: 0.000177

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: 0.000139

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000156 AC: 225 AN: 1442646 Hom.: 0 Cov.: 28 AF XY: 0.000181 AC XY: 130 AN XY: 719130

African (AFR) AF: 0.00 AC: 0 AN: 33076

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 85844

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.000196 AC: 214 AN: 1094578

Other (OTH) AF: 0.0000670 AC: 4 AN: 59708

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152102 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000301 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.76
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.32	T
PhyloP100		5.7
GERP RS		4.8
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: 0

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

Other links and lift over

dbSNP: rs147623570; hg19: chr16-87936031;