X-15776771-G-C

Variant names:

• chrX-15776771-G-C
• NM_007220.4:c.676G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007220.4(CA5B):​c.676G>C​(p.Asp226His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CA5B NM_007220.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.54

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA5B	NM_007220.4	c.676G>C	p.Asp226His	missense_variant	Exon 7 of 8	ENST00000318636.8	NP_009151.1
CA5BP1-CA5B	NR_160544.1	n.2091G>C		non_coding_transcript_exon_variant	Exon 11 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA5B	ENST00000318636.8	c.676G>C	p.Asp226His	missense_variant	Exon 7 of 8	1	NM_007220.4	ENSP00000314099.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.676G>C (p.D226H) alteration is located in exon 7 (coding exon 6) of the CA5B gene. This alteration results from a G to C substitution at nucleotide position 676, causing the aspartic acid (D) at amino acid position 226 to be replaced by a histidine (H). 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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	.;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.60
Sift	Benign	0.056	T;T
Sift4G	Uncertain	0.046	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.65		Gain of glycosylation at T223 (P = 0.1013);Gain of glycosylation at T223 (P = 0.1013);
MVP		0.75
MPC		0.62
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.76

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-15794894;