17-46171619-G-C

Variant names:

• chr17-46171619-G-C
• rs148321376
• NM_015443.4:c.525C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_015443.4(KANSL1):​c.525C>G​(p.Ser175Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S175S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KANSL1 NM_015443.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.531
• Publications: 0 publications found

Genes affected

KANSL1 (HGNC:24565): (KAT8 regulatory NSL complex subunit 1) This gene encodes a nuclear protein that is a subunit of two protein complexes involved with histone acetylation, the MLL1 complex and the NSL1 complex. The encoded protein has been implicated in a variety of cellular processes including enhancer regulation, cell proliferation, and mitosis. Mutations in this gene are associated with Koolen-de Vries Syndrome. [provided by RefSeq, May 2022]

KANSL1 Gene-Disease associations (from GenCC):

• Koolen-de Vries syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Koolen-de Vries syndrome due to a point mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP7: Synonymous conserved (PhyloP=0.531 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.525C>G	p.Ser175Ser	synonymous_variant	Exon 2 of 15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.525C>G	p.Ser175Ser	synonymous_variant	Exon 2 of 15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422882 Hom.: 0 Cov.: 35 AF XY: 0.00000142 AC XY: 1 AN XY: 706034

African (AFR) AF: 0.00 AC: 0 AN: 31536

American (AMR) AF: 0.00 AC: 0 AN: 36142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23190

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096334

Other (OTH) AF: 0.00 AC: 0 AN: 58608

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.6
DANN	Benign	0.75
PhyloP100		0.53
PromoterAI		-0.0028	Neutral

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: rs148321376; hg19: chr17-44248985;