chr17-46039088-G-C

Variant names:

• chr17-46039088-G-C
• rs139663254
• NM_015443.4:c.2331C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_015443.4(KANSL1):​c.2331C>G​(p.Pro777Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,798 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. P777P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KANSL1 NM_015443.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.768
• Publications: 2 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP7: Synonymous conserved (PhyloP=-0.768 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015443.4. 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
	KANSL1	NM_015443.4	MANE Select	c.2331C>G	p.Pro777Pro	synonymous	Exon 9 of 15	NP_056258.1
	KANSL1	NM_001193466.2		c.2331C>G	p.Pro777Pro	synonymous	Exon 9 of 15	NP_001180395.1
	KANSL1	NM_001379198.1		c.2331C>G	p.Pro777Pro	synonymous	Exon 10 of 16	NP_001366127.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.2331C>G	p.Pro777Pro	synonymous	Exon 9 of 15	ENSP00000387393.3
	KANSL1	ENST00000262419.10	TSL:1	c.2331C>G	p.Pro777Pro	synonymous	Exon 9 of 15	ENSP00000262419.6
	KANSL1	ENST00000572218.5	TSL:1	n.6548C>G		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249406 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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459798 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726288

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 44198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5116

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111678

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.2
DANN	Benign	0.69
PhyloP100		-0.77
PromoterAI		-0.025	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: rs139663254; hg19: chr17-44116454;