NM_001024845.3:c.1435+22C>T

Variant names:

• chr1-44000934-G-A
• rs2248632
• NM_001024845.3:c.1435+22C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001024845.3(SLC6A9):​c.1435+22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0883 in 1,601,346 control chromosomes in the GnomAD database, including 8,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1746 hom., cov: 33)
  • Exomes 𝑓: 0.084 (6408 hom.)
• Consequence: SLC6A9 NM_001024845.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.10
• Publications: 15 publications found

Genes affected

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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016821086).
• BP6: Variant 1-44000934-G-A is Benign according to our data. Variant chr1-44000934-G-A is described in ClinVar as Benign. ClinVar VariationId is 1179904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024845.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A9	NM_001024845.3	MANE Select	c.1435+22C>T		intron	N/A	NP_001020016.1
	SLC6A9	NM_201649.4		c.1654+22C>T		intron	N/A	NP_964012.2
	SLC6A9	NM_006934.4		c.1492+22C>T		intron	N/A	NP_008865.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A9	ENST00000372310.8	TSL:5 MANE Select	c.1435+22C>T		intron	N/A	ENSP00000361384.4
	SLC6A9	ENST00000360584.6	TSL:1	c.1654+22C>T		intron	N/A	ENSP00000353791.2
	SLC6A9	ENST00000357730.6	TSL:1	c.1492+22C>T		intron	N/A	ENSP00000350362.2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19666 AN: 152118 Hom.: 1739 Cov.: 33

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0720

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.0669

Gnomad OTH AF: 0.124

GnomAD2 exomes AF: 0.108 AC: 26380 AN: 243626 AF XY: 0.104

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.0691

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.0703

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0840 AC: 121657 AN: 1449108 Hom.: 6408 Cov.: 31 AF XY: 0.0837 AC XY: 60256 AN XY: 719804

African (AFR) AF: 0.248 AC: 8217 AN: 33158

American (AMR) AF: 0.147 AC: 6415 AN: 43668

Ashkenazi Jewish (ASJ) AF: 0.0710 AC: 1809 AN: 25480

East Asian (EAS) AF: 0.199 AC: 7840 AN: 39488

South Asian (SAS) AF: 0.114 AC: 9672 AN: 84640

European-Finnish (FIN) AF: 0.114 AC: 6048 AN: 53090

Middle Eastern (MID) AF: 0.137 AC: 781 AN: 5706

European-Non Finnish (NFE) AF: 0.0680 AC: 75128 AN: 1104052

Other (OTH) AF: 0.0961 AC: 5747 AN: 59826

GnomAD4 genome AF: 0.129 AC: 19709 AN: 152238 Hom.: 1746 Cov.: 33 AF XY: 0.131 AC XY: 9753 AN XY: 74452

African (AFR) AF: 0.242 AC: 10032 AN: 41516

American (AMR) AF: 0.122 AC: 1871 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0720 AC: 250 AN: 3470

East Asian (EAS) AF: 0.162 AC: 836 AN: 5172

South Asian (SAS) AF: 0.106 AC: 514 AN: 4830

European-Finnish (FIN) AF: 0.125 AC: 1322 AN: 10604

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.0669 AC: 4552 AN: 68016

Other (OTH) AF: 0.122 AC: 258 AN: 2116

Alfa AF: 0.111 Hom.: 413

Bravo AF: 0.135

TwinsUK AF: 0.0650 AC: 241

ALSPAC AF: 0.0682 AC: 263

ESP6500AA AF: 0.235 AC: 1036

ESP6500EA AF: 0.0656 AC: 564

ExAC AF: 0.109 AC: 13278

Asia WGS AF: 0.133 AC: 461 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.96
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.1
PROVEAN	Benign	0.74	N
REVEL	Benign	0.11
Sift	Benign	0.031	D
Sift4G	Uncertain	0.0040	D
Vest4		0.096
ClinPred		0.0031	T
GERP RS		3.3
Mutation Taster		=98/2	polymorphism (auto)

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: rs2248632; hg19: chr1-44466606; COSMIC: COSV62210331; COSMIC: COSV62210331;