rs759453731

Variant names:

• chr19-50662230-C-A
• rs759453731
• NM_016148.5:c.6221G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-50662230-C-A
• chr19-50662230-C-G
• chr19-50662230-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016148.5(SHANK1):​c.6221G>T​(p.Arg2074Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2074H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHANK1 NM_016148.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 4 publications found

Genes affected

SHANK1 (HGNC:15474): (SH3 and multiple ankyrin repeat domains 1) This gene encodes a member of the SHANK (SH3 domain and ankyrin repeat containing) family of proteins. Members of this family act as scaffold proteins that are required for the development and function of neuronal synapses. Deletions in this gene may be associated with autism spectrum disorder in males. [provided by RefSeq, Apr 2016]

SHANK1 Gene-Disease associations (from GenCC):

• autism

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4069371).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK1	NM_016148.5	c.6221G>T	p.Arg2074Leu	missense_variant	Exon 24 of 24	ENST00000293441.6	NP_057232.2
SHANK1	XM_011527013.3	c.6245G>T	p.Arg2082Leu	missense_variant	Exon 25 of 25		XP_011525315.1
SHANK1	XM_011527014.3	c.6194G>T	p.Arg2065Leu	missense_variant	Exon 23 of 23		XP_011525316.1
SHANK1	XM_047438894.1	c.4394G>T	p.Arg1465Leu	missense_variant	Exon 10 of 10		XP_047294850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK1	ENST00000293441.6	c.6221G>T	p.Arg2074Leu	missense_variant	Exon 24 of 24	1	NM_016148.5	ENSP00000293441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 246424 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.58	.;D;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	.;L;.;.
PhyloP100		1.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		0.42	B;B;.;.
Vest4		0.56
MutPred		0.23		.;Loss of solvent accessibility (P = 0.0052);.;.;
MVP		0.56
MPC		0.84
ClinPred		0.97	D
GERP RS		3.5
Varity_R		0.41
gMVP		0.51
Mutation Taster		=76/24	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: rs759453731; hg19: chr19-51165487;