1-43991892-C-G

Variant names:

• chr1-43991892-C-G
• rs751941756
• NM_152499.4:c.14C>G

Variant summary

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

The NM_152499.4(CCDC24):​c.14C>G​(p.Ser5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000374 in 1,551,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: CCDC24 NM_152499.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.363
• Publications: 0 publications found

Genes affected

CCDC24 (HGNC:28688): (coiled-coil domain containing 24) Predicted to act upstream of or within blastocyst hatching. [provided by Alliance of Genome Resources, Apr 2022]

SLC6A9 (HGNC:11056): (solute carrier family 6 member 9) The amino acid glycine acts as an inhibitory neurotransmitter in the central nervous system. The protein encoded by this gene is one of two transporters that stop glycine signaling by removing it from the synaptic cleft. [provided by RefSeq, Jun 2016]

SLC6A9 Gene-Disease associations (from GenCC):

• atypical glycine encephalopathy

  Inheritance: AR, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.04661703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC24	NM_152499.4	c.14C>G	p.Ser5Cys	missense_variant	Exon 2 of 9	ENST00000372318.8	NP_689712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC24	ENST00000372318.8	c.14C>G	p.Ser5Cys	missense_variant	Exon 2 of 9	1	NM_152499.4	ENSP00000361392.3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000136 AC: 21 AN: 154606 AF XY: 0.000170

Gnomad AFR exome AF: 0.000117

Gnomad AMR exome AF: 0.0000394

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000329

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000397 AC: 556 AN: 1399690 Hom.: 0 Cov.: 33 AF XY: 0.000404 AC XY: 279 AN XY: 690146

African (AFR) AF: 0.0000944 AC: 3 AN: 31792

American (AMR) AF: 0.0000549 AC: 2 AN: 36400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25154

East Asian (EAS) AF: 0.00 AC: 0 AN: 36014

South Asian (SAS) AF: 0.00 AC: 0 AN: 79416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5312

European-Non Finnish (NFE) AF: 0.000492 AC: 531 AN: 1079316

Other (OTH) AF: 0.000346 AC: 20 AN: 57878

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74368

African (AFR) AF: 0.0000724 AC: 3 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000254 Hom.: 0

Bravo AF: 0.000193

ExAC AF: 0.0000719 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14C>G (p.S5C) alteration is located in exon 2 (coding exon 1) of the CCDC24 gene. This alteration results from a C to G substitution at nucleotide position 14, causing the serine (S) at amino acid position 5 to be replaced by a cysteine (C). 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	0.099
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.36
PROVEAN	Benign	1.0	N
REVEL	Benign	0.073
Sift	Benign	0.36	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	B
Vest4		0.082
MVP		0.44
ClinPred		0.12	T
GERP RS		0.40
PromoterAI		0.014	Neutral
Varity_R		0.11
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs751941756; hg19: chr1-44457564;