5-35641489-G-C

Variant names:

• chr5-35641489-G-C
• rs34307272
• NM_024867.4:c.220G>C

Variant summary

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

The NM_024867.4(SPEF2):​c.220G>C​(p.Gly74Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G74C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.91
• Publications: 9 publications found

Genes affected

SPEF2 (HGNC:26293): (sperm flagellar 2) Involved in sperm axoneme assembly. Located in sperm flagellum. Implicated in spermatogenic failure 43. [provided by Alliance of Genome Resources, Apr 2022]

SPEF2 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• spermatogenic failure 43

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024867.4. 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
	SPEF2	NM_024867.4	MANE Select	c.220G>C	p.Gly74Arg	missense	Exon 3 of 37	NP_079143.3
	SPEF2	NM_144722.4		c.220G>C	p.Gly74Arg	missense	Exon 3 of 10	NP_653323.1	Q9C093-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEF2	ENST00000356031.8	TSL:1 MANE Select	c.220G>C	p.Gly74Arg	missense	Exon 3 of 37	ENSP00000348314.3	Q9C093-1
	SPEF2	ENST00000509059.5	TSL:1	c.220G>C	p.Gly74Arg	missense	Exon 3 of 19	ENSP00000421593.1	D6REZ4
	SPEF2	ENST00000282469.10	TSL:1	c.220G>C	p.Gly74Arg	missense	Exon 3 of 10	ENSP00000282469.6	Q9C093-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461566 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111818

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74214

African (AFR) AF: 0.00 AC: 0 AN: 41364

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 420

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.0085	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.094	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.22
Sift	Benign	0.088	T
Sift4G	Benign	0.085	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.68		Gain of helix (P = 0.0225)
MVP		0.37
MPC		0.25
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.43
gMVP		0.48
Mutation Taster		=68/32	polymorphism

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: rs34307272; hg19: chr5-35641591;