NM_053054.4:c.2202-8A>C

Variant names:

• chr11-66017182-T-G
• rs1326391621
• NM_053054.4:c.2202-8A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_053054.4(CATSPER1):​c.2202-8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.057 (0 hom., cov: 0)
  • Exomes 𝑓: 0.14 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CATSPER1 NM_053054.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001266
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.09
• Publications: 0 publications found

Genes affected

CATSPER1 (HGNC:17116): (cation channel sperm associated 1) Calcium ions play a primary role in the regulation of sperm motility. This gene belongs to a family of putative cation channels that are specific to spermatozoa and localize to the flagellum. The protein family features a single repeat with six membrane-spanning segments and a predicted calcium-selective pore region. [provided by RefSeq, Jul 2008]

CATSPER1 Gene-Disease associations (from GenCC):

• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 7

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000295293 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053054.4. 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
	CATSPER1	NM_053054.4	MANE Select	c.2202-8A>C		splice_region intron	N/A	NP_444282.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CATSPER1	ENST00000312106.6	TSL:1 MANE Select	c.2202-8A>C		splice_region intron	N/A	ENSP00000309052.5	Q8NEC5
	CATSPER1	ENST00000529244.1	TSL:3	n.442-8A>C		splice_region intron	N/A
	ENSG00000295293	ENST00000729053.1		n.250+258T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0572 AC: 542 AN: 9476 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.0278

Gnomad AMR AF: 0.0330

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.0238

Gnomad SAS AF: 0.0457

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0702

Gnomad OTH AF: 0.0694

GnomAD2 exomes AF: 0.0265 AC: 2398 AN: 90442 AF XY: 0.0245

Gnomad AFR exome AF: 0.0385

Gnomad AMR exome AF: 0.0426

Gnomad ASJ exome AF: 0.0212

Gnomad EAS exome AF: 0.0384

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0476

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.135 AC: 21203 AN: 156888 Hom.: 0 Cov.: 0 AF XY: 0.129 AC XY: 11693 AN XY: 90756

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

African (AFR) AF: 0.0984 AC: 381 AN: 3870

American (AMR) AF: 0.0896 AC: 950 AN: 10606

Ashkenazi Jewish (ASJ) AF: 0.0845 AC: 452 AN: 5352

East Asian (EAS) AF: 0.0640 AC: 329 AN: 5142

South Asian (SAS) AF: 0.171 AC: 4702 AN: 27526

European-Finnish (FIN) AF: 0.0750 AC: 1046 AN: 13938

Middle Eastern (MID) AF: 0.137 AC: 69 AN: 504

European-Non Finnish (NFE) AF: 0.147 AC: 12271 AN: 83696

Other (OTH) AF: 0.160 AC: 1003 AN: 6254

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0570 AC: 542 AN: 9516 Hom.: 0 Cov.: 0 AF XY: 0.0469 AC XY: 243 AN XY: 5186

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

African (AFR) AF: 0.0572 AC: 129 AN: 2254

American (AMR) AF: 0.0328 AC: 34 AN: 1038

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 14 AN: 238

East Asian (EAS) AF: 0.0239 AC: 11 AN: 460

South Asian (SAS) AF: 0.0457 AC: 15 AN: 328

European-Finnish (FIN) AF: 0.0277 AC: 14 AN: 506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 22

European-Non Finnish (NFE) AF: 0.0701 AC: 314 AN: 4480

Other (OTH) AF: 0.0649 AC: 10 AN: 154

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0127 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spermatogenic failure 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.083
DANN	Benign	0.34
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs1326391621; hg19: chr11-65784653; COSMIC: COSV106057296; COSMIC: COSV106057296;