1-244572425-A-G

Variant names:

• chr1-244572425-A-G
• rs767818910
• NM_001130957.2:c.1603A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130957.2(CATSPERE):​c.1603A>G​(p.Asn535Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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. N535H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CATSPERE NM_001130957.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.725
• Publications: 0 publications found

Genes affected

CATSPERE (HGNC:28491): (catsper channel auxiliary subunit epsilon) Located in sperm principal piece. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10608819).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130957.2. 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
	CATSPERE	NM_001130957.2	MANE Select	c.1603A>G	p.Asn535Asp	missense	Exon 11 of 22	NP_001124429.1	Q5SY80-1
	CATSPERE	NM_173807.5		c.1603A>G	p.Asn535Asp	missense	Exon 11 of 21	NP_776168.1	Q5SY80-2
	CATSPERE	NM_001242340.2		c.1150A>G	p.Asn384Asp	missense	Exon 8 of 19	NP_001229269.1	Q5SY80-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CATSPERE	ENST00000366534.9	TSL:2 MANE Select	c.1603A>G	p.Asn535Asp	missense	Exon 11 of 22	ENSP00000355492.4	Q5SY80-1
	CATSPERE	ENST00000428042.1	TSL:1	c.1363A>G	p.Asn455Asp	missense	Exon 7 of 18	ENSP00000395796.1	B1AQM6
	CATSPERE	ENST00000366533.8	TSL:1	c.1603A>G	p.Asn535Asp	missense	Exon 11 of 21	ENSP00000355491.4	Q5SY80-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454536 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724064

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105314

Other (OTH) AF: 0.0000166 AC: 1 AN: 60190

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.72
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.065
Sift	Benign	0.087	T
Sift4G	Benign	0.19	T
Polyphen		0.79	P
Vest4		0.11
MutPred		0.38		Loss of helix (P = 0.079)
MVP		0.15
MPC		0.30
ClinPred		0.19	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.40
Mutation Taster		=97/3	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: rs767818910; hg19: chr1-244735727;