chr17-60156653-G-T

Variant names:

• chr17-60156653-G-T
• rs121434552
• NM_000717.5:c.206G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000717.5(CA4):​c.206G>T​(p.Arg69Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CA4 NM_000717.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.03
• Publications: 13 publications found

Genes affected

CA4 (HGNC:1375): (carbonic anhydrase 4) 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 a glycosylphosphatidyl-inositol-anchored membrane isozyme expressed on the luminal surfaces of pulmonary (and certain other) capillaries and proximal renal tubules. Its exact function is not known; however, it may have a role in inherited renal abnormalities of bicarbonate transport. [provided by RefSeq, Jul 2008]

CA4 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 17

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-60156653-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 17609.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1097734).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000717.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA4	NM_000717.5	MANE Select	c.206G>T	p.Arg69Leu	missense	Exon 3 of 8	NP_000708.1
	CA4	NR_137422.2		n.268G>T		non_coding_transcript_exon	Exon 3 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA4	ENST00000300900.9	TSL:1 MANE Select	c.206G>T	p.Arg69Leu	missense	Exon 3 of 8	ENSP00000300900.3
	CA4	ENST00000585705.5	TSL:3	n.299G>T		non_coding_transcript_exon	Exon 3 of 3
	CA4	ENST00000586876.1	TSL:2	n.206G>T		non_coding_transcript_exon	Exon 3 of 6	ENSP00000467465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.0080
DANN	Benign	0.66
DEOGEN2	Benign	0.31	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
PhyloP100		-6.0
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.23
Sift	Benign	0.048	D
Sift4G	Benign	0.16	T
Polyphen		0.19	B
Vest4		0.078
MutPred		0.69		Loss of MoRF binding (P = 6e-04)
MVP		0.41
MPC		0.049
ClinPred		0.13	T
GERP RS		-11
Varity_R		0.39
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs121434552; hg19: chr17-58234014; COSMIC: COSV99039723; COSMIC: COSV99039723;