chr17-30203175-T-G

Variant names:

• chr17-30203175-T-G
• rs6352
• NM_001045.6:c.1815A>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BS1 BS2_Supporting

The NM_001045.6(SLC6A4):​c.1815A>C​(p.Lys605Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,612,818 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (81 hom.)
• Consequence: SLC6A4 NM_001045.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.852
• Publications: 32 publications found

Genes affected

SLC6A4 (HGNC:11050): (solute carrier family 6 member 4) This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is a target of psychomotor stimulants, such as amphetamines and cocaine, and is a member of the sodium:neurotransmitter symporter family. A repeat length polymorphism in the promoter of this gene has been shown to affect the rate of serotonin uptake. There have been conflicting results in the literature about the possible effect, if any, that this polymorphism may play in behavior and depression. [provided by RefSeq, May 2019]

SLC6A4 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC124903970 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005604863).
• BP6: Variant 17-30203175-T-G is Benign according to our data. Variant chr17-30203175-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 322529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00484 (738/152340) while in subpopulation EAS AF = 0.0331 (172/5190). AF 95% confidence interval is 0.0291. There are 12 homozygotes in GnomAd4. There are 515 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 738 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001045.6. 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
	SLC6A4	NM_001045.6	MANE Select	c.1815A>C	p.Lys605Asn	missense	Exon 14 of 15	NP_001036.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A4	ENST00000650711.1	MANE Select	c.1815A>C	p.Lys605Asn	missense	Exon 14 of 15	ENSP00000498537.1
	SLC6A4	ENST00000261707.7	TSL:1	c.1815A>C	p.Lys605Asn	missense	Exon 14 of 15	ENSP00000261707.3
	SLC6A4	ENST00000394821.2	TSL:1	c.1815A>C	p.Lys605Asn	missense	Exon 14 of 15	ENSP00000378298.2

Frequencies

GnomAD3 genomes AF: 0.00485 AC: 738 AN: 152222 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0437

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00665 AC: 1666 AN: 250632 AF XY: 0.00644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0304

Gnomad FIN exome AF: 0.0411

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00308 AC: 4499 AN: 1460478 Hom.: 81 Cov.: 29 AF XY: 0.00309 AC XY: 2242 AN XY: 726628

African (AFR) AF: 0.0000299 AC: 1 AN: 33438

American (AMR) AF: 0.0000224 AC: 1 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.0381 AC: 1511 AN: 39680

South Asian (SAS) AF: 0.000940 AC: 81 AN: 86198

European-Finnish (FIN) AF: 0.0408 AC: 2180 AN: 53396

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000476 AC: 529 AN: 1110922

Other (OTH) AF: 0.00315 AC: 190 AN: 60354

GnomAD4 genome AF: 0.00484 AC: 738 AN: 152340 Hom.: 12 Cov.: 33 AF XY: 0.00691 AC XY: 515 AN XY: 74496

African (AFR) AF: 0.0000481 AC: 2 AN: 41578

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0331 AC: 172 AN: 5190

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.0437 AC: 464 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00182 Hom.: 14

Bravo AF: 0.00157

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00618 AC: 750

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Behavior disorder Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.85
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.26
Sift	Benign	0.14	T
Sift4G	Benign	0.21	T
Polyphen		0.23	B
Vest4		0.59
MutPred		0.16		Loss of methylation at K605 (P = 4e-04)
MVP		0.28
MPC		1.2
ClinPred		0.078	T
GERP RS		-0.69
Varity_R		0.62
gMVP		0.89
Mutation Taster		=73/27	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: rs6352; hg19: chr17-28530193; COSMIC: COSV55567087; COSMIC: COSV55567087;