22-50721831-T-G

Position:

• chr22-50721831-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001372044.2(SHANK3):​c.4184T>G​(p.Val1395Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000782 in 1,558,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: SHANK3 NM_001372044.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.353

Genes affected

SHANK3 (HGNC:14294): (SH3 and multiple ankyrin repeat domains 3) This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation. Mutations in this gene are a cause of autism spectrum disorder (ASD), which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests. Mutations in this gene also cause schizophrenia type 15, and are a major causative factor in the neurological symptoms of 22q13.3 deletion syndrome, which is also known as Phelan-McDermid syndrome. Additional isoforms have been described for this gene but they have not yet been experimentally verified. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014323235).
• BP6: Variant 22-50721831-T-G is Benign according to our data. Variant chr22-50721831-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 588226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 106 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.4184T>G	p.Val1395Gly	missense_variant	24/25	ENST00000710353.1	NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000262795.7	c.3599T>G	p.Val1200Gly	missense_variant	20/22	5		ENSP00000489147	P1

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152064 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000564 AC: 91 AN: 161302 Hom.: 0 AF XY: 0.000507 AC XY: 44 AN XY: 86826

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000745

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000628

Gnomad NFE exome AF: 0.000983

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000791 AC: 1113 AN: 1406790 Hom.: 0 Cov.: 34 AF XY: 0.000783 AC XY: 544 AN XY: 694780

Gnomad4 AFR exome AF: 0.000125

Gnomad4 AMR exome AF: 0.000873

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000185

Gnomad4 NFE exome AF: 0.000955

Gnomad4 OTH exome AF: 0.000548

GnomAD4 genome AF: 0.000697 AC: 106 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.000538 AC XY: 40 AN XY: 74408

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000688

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000249 AC: 2

ExAC AF: 0.000376 AC: 43

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	SHANK3: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.029	.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.57	T
REVEL	Benign	0.10
Sift4G	Benign	0.38	T;T
Vest4		0.12
GERP RS		1.2
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs200087210; hg19: chr22-51160259;