chr7-128804724-A-G

Position:

• chr7-128804724-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022742.5(CCDC136):​c.745A>G​(p.Ser249Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,996 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: 0.0000014 (0 hom.)
• Consequence: CCDC136 NM_022742.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

Genes affected

CCDC136 (HGNC:22225): (coiled-coil domain containing 136) Predicted to be involved in acrosome assembly and single fertilization. Predicted to be integral component of membrane. Predicted to be active in acrosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22751725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC136	NM_022742.5	c.745A>G	p.Ser249Gly	missense_variant	5/18	ENST00000297788.9	NP_073579.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC136	ENST00000297788.9	c.745A>G	p.Ser249Gly	missense_variant	5/18	1	NM_022742.5	ENSP00000297788	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448996 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 719308

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00000828 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

Sep 22, 2021

The c.745A>G (p.S249G) alteration is located in exon 5 (coding exon 5) of the CCDC136 gene. This alteration results from a A to G substitution at nucleotide position 745, causing the serine (S) at amino acid position 249 to be replaced by a glycine (G). 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	0.32
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	.;.;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	T;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Uncertain	-0.071	T
MutationAssessor	Uncertain	2.3	.;.;.;M
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.7	D;D;N;N
REVEL	Benign	0.14
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.99	D;.;D;D
Vest4		0.36
MVP		0.93
MPC		0.45
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.16
gMVP		0.089

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: rs372216926; hg19: chr7-128444778;