chr8-144473998-GCTC-G

Variant names:

• chr8-144473998-GCTC-G
• rs550365735
• NM_001369769.2:c.*612_*614delCCT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001369769.2(KIFC2):​c.*612_*614delCCT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 568,502 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: KIFC2 NM_001369769.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.903
• Publications: 0 publications found

Genes affected

KIFC2 (HGNC:29530): (kinesin family member C2) Predicted to enable microtubule binding activity and microtubule motor activity. Predicted to be involved in microtubule-based movement and mitotic spindle assembly. Predicted to be located in cytoplasm. Predicted to be part of kinesin complex. Predicted to be active in microtubule cytoskeleton and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FOXH1 (HGNC:3814): (forkhead box H1) FOXH1 encodes a human homolog of Xenopus forkhead activin signal transducer-1. FOXH1 protein binds SMAD2 and activates an activin response element via binding the DNA motif TGT(G/T)(T/G)ATT. [provided by RefSeq, Jul 2008]

FOXH1 Gene-Disease associations (from GenCC):

• congenital heart malformation

  Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369769.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIFC2	NM_001369769.2	MANE Select	c.*612_*614delCCT		3_prime_UTR	Exon 18 of 18	NP_001356698.1	A0A2R8YEU8
	FOXH1	NM_003923.3	MANE Select	c.*237_*239delGAG		3_prime_UTR	Exon 3 of 3	NP_003914.1	O75593
	KIFC2	NM_145754.5		c.*551_*553delCCT		3_prime_UTR	Exon 17 of 17	NP_665697.1	Q96AC6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIFC2	ENST00000645548.2	MANE Select	c.*612_*614delCCT		3_prime_UTR	Exon 18 of 18	ENSP00000494595.1	A0A2R8YEU8
	FOXH1	ENST00000377317.5	TSL:1 MANE Select	c.*237_*239delGAG		3_prime_UTR	Exon 3 of 3	ENSP00000366534.4	O75593
	KIFC2	ENST00000301332.3	TSL:1	c.*551_*553delCCT		3_prime_UTR	Exon 17 of 17	ENSP00000301332.2	Q96AC6-1

Frequencies

GnomAD3 genomes AF: 0.000755 AC: 115 AN: 152220 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.00123 AC: 512 AN: 416164 Hom.: 2 AF XY: 0.00159 AC XY: 344 AN XY: 216762

African (AFR) AF: 0.00 AC: 0 AN: 12022

American (AMR) AF: 0.00179 AC: 30 AN: 16738

Ashkenazi Jewish (ASJ) AF: 0.00343 AC: 45 AN: 13122

East Asian (EAS) AF: 0.00 AC: 0 AN: 29768

South Asian (SAS) AF: 0.00655 AC: 242 AN: 36940

European-Finnish (FIN) AF: 0.0000354 AC: 1 AN: 28276

Middle Eastern (MID) AF: 0.00695 AC: 13 AN: 1870

European-Non Finnish (NFE) AF: 0.000601 AC: 152 AN: 252830

Other (OTH) AF: 0.00118 AC: 29 AN: 24598

GnomAD4 genome AF: 0.000748 AC: 114 AN: 152338 Hom.: 2 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74484

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00314 AC: 48 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68044

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000594 Hom.: 0

Bravo AF: 0.000703

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Holoprosencephaly sequence (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.90
Mutation Taster		=100/0	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: rs550365735; hg19: chr8-145699381;