2-213350587-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024532.5(SPAG16):c.704A>G(p.His235Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,452,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPAG16 NM_024532.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.55

Genes affected

SPAG16 (HGNC:23225): (sperm associated antigen 16) Cilia and flagella are comprised of a microtubular backbone, the axoneme, which is organized by the basal body and surrounded by plasma membrane. SPAG16 encodes 2 major proteins that associate with the axoneme of sperm tail and the nucleus of postmeiotic germ cells, respectively (Zhang et al., 2007 [PubMed 17699735]).[supplied by OMIM, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3636953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAG16	NM_024532.5	c.704A>G	p.His235Arg	missense_variant	7/16	ENST00000331683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAG16	ENST00000331683.10	c.704A>G	p.His235Arg	missense_variant	7/16	1	NM_024532.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243584 Hom.: 0 AF XY: 0.00000759 AC XY: 1 AN XY: 131712

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1452704 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 722476

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.704A>G (p.H235R) alteration is located in exon 7 (coding exon 7) of the SPAG16 gene. This alteration results from a A to G substitution at nucleotide position 704, causing the histidine (H) at amino acid position 235 to be replaced by an arginine (R). 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	0.092
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.043	T;T;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	0.97	N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.021	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.72	.;P;.;.
Vest4		0.44, 0.46, 0.49
MutPred		0.51		Gain of MoRF binding (P = 0.0078);Gain of MoRF binding (P = 0.0078);.;Gain of MoRF binding (P = 0.0078);
MVP		0.79
MPC		0.025
ClinPred		0.57	D
GERP RS		5.3
Varity_R		0.12
gMVP		0.066

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

LitVar

Other links and lift over

dbSNP: rs762154828; hg19: chr2-214215311;