chr1-43991921-C-G

Variant names:

• chr1-43991921-C-G
• rs753172586
• NM_152499.4:c.43C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152499.4(CCDC24):​c.43C>G​(p.His15Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,395,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CCDC24 NM_152499.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20427749).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152499.4. 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
	CCDC24	NM_152499.4	MANE Select	c.43C>G	p.His15Asp	missense	Exon 2 of 9	NP_689712.1	Q8N4L8-1
	CCDC24	NM_001349128.1		c.43C>G	p.His15Asp	missense	Exon 1 of 8	NP_001336057.1
	CCDC24	NM_001349127.2		c.43C>G	p.His15Asp	missense	Exon 2 of 9	NP_001336056.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC24	ENST00000372318.8	TSL:1 MANE Select	c.43C>G	p.His15Asp	missense	Exon 2 of 9	ENSP00000361392.3	Q8N4L8-1
	CCDC24	ENST00000463846.5	TSL:1	n.43C>G		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476322.1	V9GYM6
	CCDC24	ENST00000490563.5	TSL:1	n.156C>G		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000655 AC: 1 AN: 152746 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000175

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000115 AC: 16 AN: 1395598 Hom.: 0 Cov.: 33 AF XY: 0.0000102 AC XY: 7 AN XY: 687414

African (AFR) AF: 0.00 AC: 0 AN: 31640

American (AMR) AF: 0.00 AC: 0 AN: 35868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25044

East Asian (EAS) AF: 0.00 AC: 0 AN: 35854

South Asian (SAS) AF: 0.00 AC: 0 AN: 79172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48648

Middle Eastern (MID) AF: 0.000191 AC: 1 AN: 5222

European-Non Finnish (NFE) AF: 0.0000121 AC: 13 AN: 1076486

Other (OTH) AF: 0.0000347 AC: 2 AN: 57664

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000911 AC: 1

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	Uncertain	0.40
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.88	T
PhyloP100		1.7
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.095
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.018	D
Vest4		0.26
MutPred		0.32		Gain of catalytic residue at A566 (P = 0.0034)
MVP		0.52
ClinPred		0.95	D
GERP RS		3.0
PromoterAI		0.12	Neutral
Varity_R		0.43
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs753172586; hg19: chr1-44457593;