X-15750142-C-T

Variant names:

• chrX-15750142-C-T
• NM_007220.4:c.119C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007220.4(CA5B):​c.119C>T​(p.Thr40Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,669 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CA5B NM_007220.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

Genes affected

CA5B (HGNC:1378): (carbonic anhydrase 5B) 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. This gene encodes carbonic anhydrase 5B. CA5B, and the related CA5A gene, has its expression localized in the mitochondria though CA5B has a wider tissue distribution than CA5A, which is restricted to the liver, kidneys, and skeletal muscle. A carbonic anhydrase pseudogene (CA5BP1) is adjacent to the CA5B gene and these two loci produce CA5BP1-CA5B readthrough transcripts. [provided by RefSeq, Jan 2019]

CA5BP1-CA5B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA5B	NM_007220.4	c.119C>T	p.Thr40Ile	missense_variant	Exon 2 of 8	ENST00000318636.8	NP_009151.1
CA5BP1-CA5B	NR_160544.1	n.883C>T		non_coding_transcript_exon_variant	Exon 5 of 12
CA5BP1-CA5B	NR_160545.1	n.883C>T		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA5B	ENST00000318636.8	c.119C>T	p.Thr40Ile	missense_variant	Exon 2 of 8	1	NM_007220.4	ENSP00000314099.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096669 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362047

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119C>T (p.T40I) alteration is located in exon 2 (coding exon 1) of the CA5B gene. This alteration results from a C to T substitution at nucleotide position 119, causing the threonine (T) at amino acid position 40 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	.;T;.;T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.64	T;.;T;T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.4	.;L;.;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	N;N;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.19	.;B;.;B
Vest4		0.25, 0.25
MutPred		0.57		Gain of catalytic residue at T40 (P = 0.0641);Gain of catalytic residue at T40 (P = 0.0641);Gain of catalytic residue at T40 (P = 0.0641);Gain of catalytic residue at T40 (P = 0.0641);
MVP		0.88
MPC		0.40
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.15
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-15768265;