chr1-43991942-C-T

Variant names:

• chr1-43991942-C-T
• rs1474045296
• NM_152499.4:c.64C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001349129.1(CCDC24):​c.-160C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000432 in 1,388,412 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: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: CCDC24 NM_001349129.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.444
• 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: Unknown, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05651191).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349129.1. 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
	CCDC24	NM_152499.4	MANE Select	c.64C>T	p.Arg22Cys	missense	Exon 2 of 9	NP_689712.1	Q8N4L8-1
	CCDC24	NM_001349129.1		c.-160C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001336058.1
	CCDC24	NM_001349128.1		c.64C>T	p.Arg22Cys	missense	Exon 1 of 8	NP_001336057.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC24	ENST00000372318.8	TSL:1 MANE Select	c.64C>T	p.Arg22Cys	missense	Exon 2 of 9	ENSP00000361392.3	Q8N4L8-1
	CCDC24	ENST00000463846.5	TSL:1	n.64C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476322.1	V9GYM6
	CCDC24	ENST00000490563.5	TSL:1	n.177C>T		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000271 AC: 4 AN: 147726 AF XY: 0.0000128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000432 AC: 6 AN: 1388412 Hom.: 0 Cov.: 33 AF XY: 0.00000293 AC XY: 2 AN XY: 682926

African (AFR) AF: 0.00 AC: 0 AN: 31444

American (AMR) AF: 0.000142 AC: 5 AN: 35166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24732

East Asian (EAS) AF: 0.00 AC: 0 AN: 35656

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5040

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071914

Other (OTH) AF: 0.00 AC: 0 AN: 57304

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.44
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.034
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.014	D
Polyphen		0.10	B
Vest4		0.19
MutPred		0.37		Loss of MoRF binding (P = 0.0037)
MVP		0.24
MPC		0.045
ClinPred		0.20	T
GERP RS		2.6
PromoterAI		-0.11	Neutral
Varity_R		0.21
gMVP		0.37
Mutation Taster		=93/7	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: rs1474045296; hg19: chr1-44457614;